Conference Program and Abstracts

Molecular Targets for Predictive
and Personalized Medicine
of Cancer
6th Annual IMPPC Conference
Barcelona
8-10 April 2015
WELCOME
Recent advances in genome technology have made it possible
in principle to identify all the genetic and epigenetic alterations
accumulated in cancer cells during the process of multistage
carcinogenesis. Based on this knowledge, various inhibitors
specific to activated and/or mutated gene products have been
developed and applied to treat cancer patients carrying specific
somatic genetic and epigenetic alterations. In several types of
cancer the prognosis of patients has been considerably improved
by the integration of this type of treatment. Molecular markers are
now therefore, important for the classification of cancer and in
particular at the moment of definition of the treatment strategy for
each patient.
Additionally, genome-wide association studies have made it
possible to identify many genetic polymorphisms associated with
susceptibility to several types of cancer. Such knowledge will be
applicable in the near future to the development of novel ways to
predict cancer and eventually prevent it in individuals at highrisk. For these reasons it has become even more important to
identify molecular targets useful for cancer prediction, prevention,
diagnosis and the development of personalized treatments.
In the 6th IMPPC Annual Conference, we will discuss the recent
progress in studies on molecular targets for predictive and
personalized medicine of human cancer. Some outstanding
international scientists in the field, ranging from basic to clinical
specialists, will participate and we sincerely hope that you can
also join us for this important conference in cancer medicine.
The Organizers
Rafael Rosell, Catalan Institute of Oncology (ICO)
Jun Yokota, Institute of Predictive and Personalized
Medicine of Cancer (IMPPC)
WELCOME
3
CONTENTS
Welcome............................... 3
Contents............................... 5
Notes on our venue................ 6-7
Program................................ 8-13
Speaker Abstracts................. 14-57
Poster Abstracts.................... 58-90
Delegate Contacts................. 92-97
CONTENTS
5
LA CASA
DE CONVALESÈNCIA
The Casa de Convalescència is a beautifully restored building
from the Barcelona Modernist period (end of the XIX Century).
The building is part of the facilities of the Autonomous University
of Barcelona. It is on the famous Hospital Sant Pau and Santa
Creu campus, much of it now restored to its former glory; the
enclosure is now a designated World Heritage Site.
Wifi connection
Find the “Casa de la Convalescència” network
User: imppc2015
Password: wifi2015
No smoking area
Please note that we are on the hospital campus. There is strictly
no smoking anywhere except the garden at the front of the
building. Please use ashtrays and do not leave any litter
on the ground.
PLEASE DO NOT SIT ON THE GRASS, even at lunchtime.
We know it is very tempting but it is also very delicate.
Toilets
These are downstairs in the entrance hall at the back behind
the staircase. Ladies to the left, gentleman to the right as you
go down.
Telephones
Please silence your telephones during sessions.
NOTES ON OUR VENUE
7
PROGRAM
WEDNESDAY 8 APRIL
16.00-16.10
Opening of the conference
Welcome Remarks: Manuel Perucho
Introduction: Jun Yokota
16.00-17.50
Session 1: Target Cancer Genes (1)
Chair: Manuel Perucho
16.10-16.50
Mariano Barbacid (CNIO, Madrid, Spain)
Targeting Cancer Genes: The K-Ras signaling pathway in lung
and pancreatic tumors
16.50-17.20
Laura Soucek (VHIO, Barcelona, Spain)
Preclinical validation of Myc inhibition by a new generation of
Omomyc-peptides
17.20-17.50
Montse Sanchez-Céspedes (IDIBELL, Barcelona, Spain)
Dissection of the BRG1 and MYC/MAX biological connection
and its use in lung cancer therapeutics
17.50-18.20
Coffee break
PROGRAM
18.20-20.00
Session 2: Genome-wide Studies
Chair: Agusti Barnadas
18.20-18.30
Agusti Barnadas (Hospital Sant Pau, Barcelona, Spain)
Introduction to Hospital Sant Pau
18.30-19.00
Jun Yokota (IMPPC, Barcelona, Spain)
MYC inhibition as a therapeutic strategy in small
cell lung cancer
19.00-19.30
Martin Sos (University of Cologne, Germany)
Targeting molecular dependencies in cancer
19.30-19.45
Roberto Mosca (IRB, Barcelona, Spain)
dSysMap: exploring the edgetic role of disease mutations
19.45-20.00
Santi Gonzalez (BSC, Barcelona, Spain)
Characterisation of complex rearrangements in
cancer genomes
9
THURSDAY 9 APRIL
9.00- 10.40
Session 3: Prediction Markers (1)
Chair: Laura Soucek
09.00-09.40
Allan Balmain (UCSF, San Francisco, USA)
Modelling “Precision Cancer Medicine” in the mouse.
09.40-10.10
Eduard Serra (IMPPC, Barcelona, Spain)
Genomics of Peripheral Nerve Sheath Tumors
in Neurofibromatosis
10.10-10.40
Fast Track Presentations of Posters Session 1
10.40-11.00
Coffee break and Poster Session
11.00-13.00
Session 4: Target Cancer Genes (2)
Chair: Montse Sanchez-Céspedes
11.00-11.40
Kristiina Vuori (SBMRI, La Jolla, USA)
Identification of Novel Cancer Targets in Glioblastoma
11.40-12.20
Curtis C. Harris (NCI, Maryland, USA)
Interweaving the threads of p53, microRNA, DNA methylation
and inflammation networks into the tapestry
of cancer and aging
12.20-13.00
Fast Track Presentations of Posters Session 2
13.00- 14:30
PROGRAM
Lunch and Poster Session
14.30-16.40
Session 5: Prediction Markers (2)
Chair: Curtis C. Harris
14.30-14.45
Silvestre Vicent (CIMA, Pamplona, Spain)
An integrative cross species, cross tumors gene
expression approach unveils novel oncogene dependencies
in mutant KRAS tumors
14.45-15.00
Johanna Samuelsson (Active Motif Inc., San Diego, USA)
Transposase-Assisted Chromatin immunoprecipitation
(TAM‐ChIP) as a tool for the simultaneous investigation
of multiple targets in FFPE cancer tissues
15.00-15.30
Pedro Medina (GenyO, Granada, Spain)
MicroRNAs, Chromatin Remodeling complexes, and cancer
15.30-16.00
Eduard Eyras (UPF, ICREA, Barcelona, Spain)
RNA processing alterations as drivers and prognostic markers
of cancer
16.00-16.40
Carlo Croce (University of Ohio, USA)
Causes and consequences of microRNA dysregulation
in cancer
16.40-18.00
Poster Session
11
FRIDAY 10 APRIL
9.00-10.30
Session 6: Drug Discovery
Chair: Rafael Rosell
09.00-09.30
Aleix Prat (Hospital Clínic, Barcelona, Spain)
Clinical Implications of the Intrinsic Molecular Subtypes of
Breast Cancer
09.30-10.00
Egbert Smit (VU University, Amsterdam, Netherland)
Molecular imaging using radiolabeled drugs in lung cancer
10.00-10.30
Robert Torka (Max-Planck, Munich, Germany)
Compensatory mechanisms to AXL Receptor Tyrosine Kinase
Inhibitors
10.30-11.00
Coffee break
11.00-13.00
Session 7: Target Therapy
Chair: Jun Yokota
11.00-11.40
Takashi Kohno (NCCRI, Tokyo, JAPAN)
RET fusion and chromatin remodeling genes. targets for
precision lung cancer medicine
11.40-12.20
Rafael Rosell (ICO, Barcelona, Spain)
Bypass tracks in lung cancer resistance
12.20-13.00
Webster Cavenee (UCSD, San Diego, USA)
A novel “hide and seek” mechanism driving
therapeutic resistance
13.00
PROGRAM
Closing Remarks: Rafael Rosell
13
Invited Talk
Mariano Barbacid
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO),
Madrid, Spain
Targeting Cancer Genes: The K-Ras signaling pathway in lung and
pancreatic tumors
K-RAS oncogenes have been implicated in one fifth of all human cancers including those
with worse prognosis such as lung and pancreatic ductal adenocarcinoma.
In an attempt to identify those critical targets responsible for mediating K-RAS oncogenic
signaling in these tumors, we have developed genetically engineered mouse strains that
upon expression of a resident K-Ras oncogene, closely recapitulate the natural history
of these human tumors. In previous studies (Puyol et al., Cancer Cell 2010; Blasco et al.,
Cancer Cell 2011; Navas et al., Cancer Cell 2012), we crossed these strains with mice
that carried lox-Cre conditional knock out loci encoding potential therapeutic targets in
order to determine whether they were required for K-Ras induced tumor development.
These studies led us to validate the c-Raf and Cdk4 kinases as essential targets for
the development of lung adenocarcinomas. Likewise, we demonstrated that the EGF
Receptor and c-Raf were absolutely essential for the development of pancreatic ductal
adenocarcinomas. Now, we have generated new strains of mice in which expression of
the resident K-Ras oncogene as well as ablation of the p53 tumor suppressor is mediated
by the FLp(o)/frt system, thus allowing us to temporally separate tumor induction from
target ablation. Moreover, we have generated lox-Cre conditional knock-in strains that
direct the expression of kinase dead isoforms instead of causing protein ablation. This
new experimental system is allowing us to inactivate the above targets, as well as other
kinases such as PI3Kinase and mTOR, in tumor-bearing mice to better evaluate their
therapeutic potential with the ultimate goal to serve as guide for the design of future
clinical trails.
SPEAKER ABSTRACTS
15
Invited Talk
Laura Soucek
Marie-Eve Beaulieu1, Toni Jauset, Daniel Massó-Vallés1, Jonathan R. Whitfield1, Erika
Serrano1, Martin Montagne2, Pierre Lavigne2, Antonio Villaverde3, Mireia Pesarrodona3,
Esther Vazquez3, and Laura Soucek1 1Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 2University of Sherbrooke,
Sherbrooke, Canada; 3Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de
Barcelona, Spain
Preclinical validation of Myc inhibition by a new generation of
Omomyc-peptides
Deregulated Myc is associated with most human cancers suggesting that its inhibition
would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition
displays extraordinary therapeutic benefit in various transgenic mouse models of cancer
(i.e. skin, lung, pancreatic cancer and glioma) and causes only mild, well-tolerated and
reversible side effects in normal tissues. Furthermore, we demonstrated that Myc has
a non-degenerate function in cancer that cannot be replaced by other pathways, even
in the most aggressive p53-null tumors. Therefore, Myc could be targeted safely and
successfully without eliciting resistance to therapy.
For these studies we employed a dominant negative inhibitor of Myc, called Omomyc,
which is an effective inhibitor of Myc transactivation function both in vitro and in vivo.
Omomyc has so far been utilized exclusively as a transgene and served as a successful
proof of principle. Here we discuss our current research with Omomyc and our efforts
to develop a clinically viable approach to Myc inhibition. One is based on the direct
use of Omomyc itself as a peptide since we have discovered that it natively possesses
cell-penetrating activity and it rapidly biodistributes to the lung and brain after intranasal
administration. We are finding that the Omomyc peptide - like its transgenic counterpart
before – has a therapeutic impact and we are continuing with the preclinical validation
of this innovative therapeutic approach to pharmacological Myc inhibition. The second
approach takes advantage of state-of-the-art nanocarrier technology to deliver Omomyc
systemically, that can be combined with tumour-targeting ligands. These two novel Myc
inhibition strategies have the potential to be translated rapidly to the clinic.
SPEAKER ABSTRACTS
17
Invited Talk
Montse Sanchez-Céspedes
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge
Biomedical Research Institute (IDIBELL), Barcelona, Spain.
Dissection of the BRG1 and MYC/MAX biological connection and its
use in lung cancer therapeutics
Lung cancer is the first cause of death due to cancer in most western countries, in
part because of the low efficacy of most current therapies. Previously, we reported that
one third of the lung tumors of the non-small cell lung cancer type (NSCLC) endure
inactivation of BRG1, which constitutes the fourth most commonly altered gene in
this type of cancer. The BRG1 gene codes for a member of the SWI/SNF chromatin
remodeling complex, and its role in cancer development is still poorly understood, which
hinders its potential use in clinical settings. Here, I report our discovery on how the
expression of wild type BRG1 in lung cancer cells restores the gene expression signature
of normal lung and the capability to respond to retinoic acid and glucocorticoids. This
supports that BRG1 inactivation enables the cancer cell to sustain undifferentiated gene
expression programs and prevent its response to environmental stimuli. On the other
hand, small cell lung cancer (SCLC) accounts for one-fifth of lung cancer diagnoses
and is a highly aggressive malignancy. However, our knowledge of SCLC genetics is
still very limited, amplification of L-MYC, N-MYC and C-MYC being some of the well
established gene alterations. In this presentation I will also report our discovery of biallelic
and tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC.
Alterations in MAX were mutually exclusive with alterations at MYC and BRG1. We also
reveal a direct functional connection between MAX and the chromatin remodeler BRG1
and a preferential toxicity of the deletion of BRG1 in MAX-deficient lung cancer cell lines,
suggesting a synthetic lethal type of interaction between MAX and BRG1. Taken together,
these observations demonstrate that an aberrant SWI/SNF-MYC network is essential for
lung cancer development, and suggest therapeutic strategies for patients with MAXdeficient tumors.
SPEAKER ABSTRACTS
19
Jun Yokota
Cancer Genome Biology Group
IMPPC
MYC Inhibition as a Therapeutic Strategy in Small Cell Lung Cancer
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The prognosis
of SCLC patients is very poor with only 5% of SCLC patients survived beyond 5
years after diagnosis. Importantly, the prognosis has not been improved over the last
four decades. This could be due to the fact that most of cases are diagnosed after
metastasis, thus, are usually treated by combination of chemotherapy and radiotherapy,
and that proper targeting therapies for SCLC have not yet been developed. Although
extensive genome-wide mutational analyses have been performed in SCLC, targetable
genetic alterations have not been well defined. Except for the genetic inactivation of the
TP53 and RB1 genes and amplification of the MYC family genes, the spectra of genes
with high mutation frequencies are considerably different among studies, and no known
druggable mutations have been identified to date. Therefore, to obtain further information
on genes targetable for therapy of SCLC patients, we should further apply several newly
developed genome-wide analyses with a larger number of clinical SCLC cases. Since
the TP53 and RB1 genes are inactivated in nearly 100% of SCLC cases and one of the
three MYC family genes, MYC, MYCN and MYCL1, is amplified and overexpressed
mutually exclusively in approximately 20% of SCLC cases, development of target
therapy for inactivated TP53 and RB1 and amplified MYC would be also important for
the improvement of patients’ outcomes in this disease. For these reasons, we are now
involved in the following two projects for the development of predictive and personalized
medicine of SCLC. One is the identification of novel molecular targets for treatment of
SCLC, and the other is the development of novel targeting therapies for SCLC patients.
I will present our recent data on MYC Inhibition as a possible therapeutic strategy
in SCLC.
SPEAKER ABSTRACTS
21
Invited Talk
Martin L. Sos
1 Department of Translational Genomics, Center of Integrated Oncology Köln–Bonn,
University of Köln, 50924 Köln, Germany 2 Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology
Köln Bonn, 50924 Cologne, Germany
Translating the dynamics of resistance signaling in cancer into
therapeutic strategies
Despite the development of a number of potent targeted therapeutics, only a fraction of
patients presenting with oncogenically dependent tumors benefits from the treatment
with these drugs. The on-target activity, intra-tumoral pathway resiliency and the
evolutionary selection of resistant clones mainly dictate the efficacy of targeted inhibitors.
We used integrated chemo-genomics and chemo-proteomics approaches to gain insights
into the dynamics of these processes and to define novel cancer vulnerabilities that may
overcome resistance in these tumors. In RAF inhibitor primary resistant BRAF-mutant
cancer cells we uncovered differential pathway resiliency in response to inactivation of
MAPK signaling. We identify the assembly of RAS/RAF/MEK complexes and cytokine
secretion as critical forces to override RAF-MAPK pathway inhibitor efficacy. To capture
the emergence of resistance in EGFR- mutant and ALK-fusion positive lung cancer, we
analyzed the genomes, exomes, trascriptomes and the cellular phenotype of tumors
that became resistant to TKI treatment. These analyses allowed the identification of
previously unknown resistance mechanisms as well as a heterogenic response pattern
of known resistance mechanisms in these tumors. Overall, our data provide a genomeand phosphoproteome-wide view of the adaptive process of resistance and reveals
translatable strategies toward improvement of the efficacy of individualized therapies in
these patients.
SPEAKER ABSTRACTS
23
Short Talk
Roberto Mosca
Roberto Mosca (1) (presenting author), Jofre Tenorio-Laranga (1), Roger Olivella (1), Victor
Alcalde (1), Arnaud Cèol (1,2), Montserrat Soler-López (1) and Patrick Aloy (1,3)
1) Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in
Biomedicine (IRB Barcelona), Spain (2) Center for Genomic Science of IIT@SEMM, Istituto
Italiano di Tecnologia (IIT), Italy (3) Institució Catalana de Recerca i Estudis Avançats
(ICREA), Spai
dSysMap: exploring the edgetic role of disease mutations
Understanding the intricate genotype-to-phenotype relationships behind human diseases
is fundamental for the development of personalized therapies, and requires bridging
molecular knowledge with a more systemic view of biological processes. Here, we
present dSysMap, a resource for the systematic mapping of disease-related missense
mutations on the human structural interactome. dSysMap summarizes mutational
data in a systemic context, and provides a unique tool to the biologist to easily grab
the molecular relationships between diseases and formulate hypotheses about their
mechanism of action. Overall, we provide contextual information for 24,000 mutations
related to 2,800 diseases, many of which lay on protein-protein interfaces and are likely to
induce edgetic perturbations. Unlike static databases, dSysMap allows to upload newly
discovered mutations so that disease context can be readily incorporated into primary
sequencing studies. Furthermore, we illustrate the value of dSysMap through the detailed
analysis of the Loeys-Dietz syndrome, and experimentally validate the edgetic role of 9
disease mutations on the interaction neighborhood of 5 different proteins, suggesting
hypothesis as to their molecular mechanisms. Reference Mosca R, Tenorio-Laranga J,
Olivella R, Alcalde V, Cèol A, Soler-López M and Aloy P, dSysMap: exploring the edgetic
role of disease mutations, 2015, Nature Methods, March issue, in press. http://dsysmap.
irbbarcelona.org
SPEAKER ABSTRACTS
25
Short Talk
Santi Gonzalez
Santi Gonzalez (presenting author) Marta Munar (1) Silvia Beà (2) Itziar Salaverria (2) Elias
Campo (2) David Torrents (1)
(1) Barcelona Supercomputing Center (2) Hospital Clínic
Characterisation of complex rearrangements in Cancer genomes
The study of genome reorganization events in cancer is crucial for the understanding of
the underlying functional processes behind tumor formation and progression. Recent
initiatives in the field of cancer research are focused in the sequencing of large amount
of samples, giving us the opportunity to directly explore the sequence and to identify
the genetic variation associated to tumor formation and progression. Although the
identification of somatic single nucleotide variants is possible at high level of accuracy,
existing methods for the detection of structural variation show important limitations, both
at the level of sensitivy and also specificty, leaving a large portion of rearrangements
undetected. In order to overcome these limitations, we have developed SMUFIN (for
Somatic Mutation FInder), which is able to identify nearly all types of somatic variation
in a particular tumor genome from its direct comparison with the corresponding normal
genome of the same individual. Initial application to specific tumors have allowed us
the characterization, at base pair resolution, of solid and blood tumors, defining in detail
chromotriptic and chromoplectic chromosome organization patterns. Further application
to 150 whole genomes of chronic lymphocytic leukemia samples have allowed us to
characterize the somatic structural variation in this tumor providing interesting insight into
the possible mechanisms of chromatine reorganization. As next step, and in the context
of the largest initiative of cancer genome sequencing, PanCAncer, we are analyzing up
to 2500 tumor genomes, which is providing enough power to identify recurrent patterns
and characteristic rearrangement events to infer functional consequences related to
chromatin structure, as well as in relation to tumor formation and progression.
SPEAKER ABSTRACTS
27
Invited Talk
Allain Balmain
Genome Analysis Core Facility, UCSF Helen Diller Family Comprehensive Cancer Center
Modelling “Precision Cancer Medicine” in the mouse.
Humans are genetically highly heterogeneous – each individual has her/his own set
of inherited polymorphisms that affect susceptibility to disease development, and in
particular to cancer. Different germline polymorphisms can also affect cancer subphenotypes, such as inflammation, metabolism, or obesity, each of which is associated
with cancer development or progression. In addition to this germline complexity, somatic
mutations and genetic heterogeneity are major contributors to prognosis and patient
outcomes after treatment with cancer drugs. Nevertheless, most mouse cancer models
employ inbred mouse strains and tumors are often generated by genetic engineering
of only one or two driver genes. These models therefore do not reflect the enormous
heterogeneity of human cancers.
We have tried to circumvent many of the above problems by using genetically
heterogeneous mouse populations generated by crossing different strains. In these
mice, we chemically induce carcinomas driven by either Kras or Hras mutations. These
models reflect somatic heterogeneity in human cancers as they have a high frequency
of genome-wide point mutations, as opposed to GEM models initiated by the same
Ras mutations, which carry copy number changes but almost no point mutations.
Development of malignant carcinomas of the skin provides a unique opportunity to mimic
the clinical course of the human disease: primary tumors can be surgically removed,
leaving the mice alive to develop multiple metastases at distant sites including the lymph
nodes, lung, chest wall and visceral organs. Genetic mapping has revealed that tumor
initiation, progression and metastasis are under separate genetic control, while gene
expression network analysis has identified candidate genes that may be exploited in
cancer prevention or therapy.
SPEAKER ABSTRACTS
29
Invited Talk
Eduard Serra
Genetic Variation and Cancer Group, IMPPC
Genomics of Peripheral Nerve Sheath Tumors in Neurofibromatosis
One of the major clinical complications of Neurofibromatosis type 1 (NF1) patients is
the development of different tumor types that arise in nervous and non-nervous tissues,
both in childhood and adulthood. The peripheral nervous system is particularly affected,
with the development of multiple dermal neurofibromas (DNFs), plexiform neurofibromas
(PNFs) and malignant peripheral nerve sheath tumors (MPNSTs). PNFs affect about
30% of NF1 patients, are thought to be congenital and can affect large regions of
tissue since they develop from multiple fascicles or large nerves. DNFs do not progress
towards malignancy but certain PNFs transform into MPNSTs. Approximately 8–13%
of NF1 patients develop MPNSTs, which are the leading cause of NF1-related mortality.
Bi-allelic inactivation of the NF1 gene is a key event in tumor initiation for both benign
and malignant lesions. DNFs and PNFs are composed of different cell types, but only
Schwann cells bear a double inactivation of the NF1 gene. Due to its invasive growth,
propensity to metastasize, and limited sensitivity to chemotherapy and radiation, MPNST
has a poor prognosis. Surgical resection is the basis of MPNST clinical management. The
5-year survival rate of NF1 patients with MPNST is 21%, compared to 42% for sporadic
cases. We are applying different genomic techniques, at constitutional and somatic
levels, to better understand tumor predisposition, tumor progression and cell type of
origin of these peripheral nerve sheath tumors, and to develop personalized in vitro and in
vivo therapeutic strategies.
SPEAKER ABSTRACTS
31
Invited Talk
Kristiina Vuori
Darren Finlay1, Harshil Dhruv2, Jeff Kiefer2, Seungchan Kim2, Michael Berens2 and Kristiina
Vuori1
(1) Sanford-Burnham Medical Research Institute, La Jolla, CA, (2) TGen, Phoenix, AZ.
Identification of Novel Cancer Targets in Glioblastoma
Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a poor prognosis
and limited therapeutic options. GBM is the most common malignant brain tumor and
the search for novel therapeutic targets and/ or the repurposing of already existing
drugs to treat the disease is therefore of an unmet medical need. We describe here a
comprehensive multidisciplinary approach to identifying said targets and ergo potential
therapies. We have applied a novel analytical strategy to The Cancer Genome Atlas
(TCGA) GBM expression data to stratify GBM into novel subtypes we call molecular
contexts, or mCs. Subsequently, a panel of patient-derived GBM xenografts was ascribed
to these subtypes. Utilizing a technique we term Chemical Biology Fingerprinting, or CBF,
short-term three-dimensional cultures derived from these clinically-relevant preclinical
models were screened for chemosensitivity with a deeply annotated, yet clinically
relevant, library of chemical compounds. Agents that were statistically more cytotoxic to
one subtype than another were then re-tested in true drug dose response experiments
to confirm sensitivity. Important drug vulnerabilities have been identified in a subtypespecific manner that are being further developed to clinical use. In summary, we
demonstrate a subclassification of GBM into novel molecular contexts (mCs) and show
that these contexts are differentially sensitive to clinically relevant drugs.
SPEAKER ABSTRACTS
33
Invited Talk
Curtis C. Harris
Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, MD 20892-4258, USA
Interweaving the Threads of the p53, MicroRNA, and Inflammation
Networks into the Tapestry of Aging and Cancer - A Precision
Medicine Strategy
The p53 network is an intrinsic monitoring and responsive pathway of telomeric
attrition involved in cellular aging and senescence. Cellular senescence is also a tumor
suppressive mechanism that can be activated by p53. We are studying the molecular
mechanisms of cellular senescence in normal and malignant human cells. A switch in
the expression patterns of p53 isoforms, a dominant negative Δ133Np53 and a cotransactivator p53beta of full-length p53, can cause cellular senescence in vitro and is
also associated with aging of CD8 positive circulating Tcells and the transition of benign
to malignant human cancers in vivo.
Chronic infection and inflammation contribute to the etiology and pathogenesis of about
1 in 4 of all cancer cases. Mediators of the inflammatory response, e.g., cytokines,
free radicals, prostaglandins, non-coding RNAs, and growth factors, can induce
genetic and epigenetic changes including point mutations in tumor suppressor genes,
DNA methylation and post translation modifications, causing alterations in critical
pathways responsible for maintaining the normal cellular homeostasis and leading to
the development and progression of cancer. DNA damage by ionizing radiation and free
radicals can modulate microRNA expression. IL-6 and IL-8 cooperate with microRNAs in
the induction of cellular senescence in benign tumors and as autocrine growth factors in
carcinoma.
Expression of microRNAs and inflammatory genes are mechanistic-based biomarkers
of cancer risk, diagnosis, prognosis, and therapeutic outcome. We are especially
interested in the interaction of inflammatory cytokines, p53 isoforms, and microRNAs as
prognostic classifiers of early stage cancers and their functional role in the development
of micrometastases.
SPEAKER ABSTRACTS
35
Short Talk
Silvestre Vicent
Adrian Vallejo (1), Naiara Perurena (1), Pawel Mazur (2), Elizabeth Guruceaga (1), Susana
Martinez-Canarias (1), Carolina Zandueta (1), Maria Ujue Latasa (1), Maria Jose Pajares (1),
Jackeline Agorreta (1), Dana Gwinn (2), Leanne Sayles (2), Joseph Kissil (3), Jesper Andersen
(4), Purvesh Khatri (2), Matias Avila (1), Carmen Berasain (1), Luis Montuenga (1), Alejandro
Sweet-Cordero (2), Julien Sage (2), Fernando Lecanda (1), Silvestre Vicent (1)(Presenting
Author) (1) Center for Applied Medical Research (CIMA), SPAIN (2) Stanford University School of
Medicine, USA (3) The Scripps Research Institute, USA. (4) University of Copenhagen,
DENMARK
An integrative cross-species, cross-tumors gene-expression
approach unveils novel oncogene dependencies in mutant KRAS
tumors
KRAS is the most frequently mutated oncogene in human cancer. KRAS mutations are
directly responsible for tumor initiation and maintenance of many epithelial cancers
including those of the lung, pancreas and colon, thus KRAS represents a clinically
relevant target. Efforts to tackle oncogenic KRAS have been unsuccessful for more than
25 years including recent strategies to inhibit KRAS directly. It is therefore critical to
identify targets elicited by the KRAS signaling pathway that could unveil new therapeutic
candidates. Using an innovative cross-species, cross-tumors gene-expression approach
including 1) multiple mouse and human experimental systems, and 2) panels of wellannotated clinical specimens of various tumors harboring KRAS mutations, we uncovered
a list of 8 candidate genes recurrently upregulated across KRAS-driven tumors. High
expression of the 8-gene signature was a marker of poor survival in tumors harboring
KRAS mutations such as lung adenocarcinoma (LAC). Within this 8-gene set, the
transcription factor FOSL1 recurrently appeared as a poor marker of survival in multiple
LAC data sets compared to other genes. Of note, stratification of patients based on
FOSL1 expression and KRAS mutation revealed that patients expressing high FOSL1
and KRAS oncogene had the worse survival. Follow-up experiments in a panel of
LAC cell lines showed a genotype specific expression of FOSL1 in mouse and human
mutant KRAS cells, and further analysis of genetically-engineered mouse models of LAC
revealed upregulation of fosl1 in advanced tumors. Loss-of-function functional analyses
in vitro and in vivo determined that mutant KRAS cell lines are more sensitive to FOSL1
loss than wild type cells. Our results indicate that FOSL1 is a clinically and functionally
relevant gene for KRAS-driven LAC carcinogenesis. Experiments to resolve the cellular
and molecular mechanisms behind these observations are underway, as well as to
characterize the transversal role of FOSL1 in other cancer types.
SPEAKER ABSTRACTS
37
Short Talk
Johanna Samuelsson
Johanna K. Samuelsson1, Mike Choob1, Sergio Alonso2, Paul Labhart1, Jacob Dabrowski1,
Brian Egan1, Terry Kelly1 and Manuel Perucho2. 1: Active Motif Inc. Carlsbad, California, USA. 2: Institute of Predictive and Personalized
Medicine of Cancer (IMPPC). Campus Can Ruti, Badalona, Barcelona, Spain.
Transposase-Assisted Chromatin immunoprecipitation (TAM-ChIP) as
a tool for the simultaneous investigation of multiple targets in primary
formalin-fixed, paraffin-embedded (FFPE) cancer tissues
Colorectal cancer is the third most common cancer and the fourth leading cause of
cancer-related deaths in the world. Genetic and epigenetic alterations and their crossinteractions are germane to colorectal cancer. Gaining further insights into these
alterations is crucial for understanding disease susceptibility, initiation and progression.
ChIP coupled with high-throughput sequencing is a powerful tool for genome-wide
analysis of in vivo protein-DNA interactions. However, ChIP is technically demanding
and currently limited mainly to cultured cells and model systems. Identifying alterations
in histone modification profiles directly in primary tissues would be highly valuable. We
initially developed a highly sensitive ChIP protocol specifically for FFPE samples, the gold
standard for storage of pathology samples. The genome-wide comparison of H3K4me3
and H3K27me3 levels in normal and tumor human colon FFPE samples identified various
cancer specific alterations. Correlating these ChIP results with DNA methylation and
mutation data provided a multi-level epigenetic and genetic profiling of FFPE samples
highlighting the value of performing ChIP in primary tissue samples.To potentially allow
the simultaneous investigation of multiple targets in the same tissue sample we utilized
the ‘cut and paste’ ability of the Tn5 transposase to develop Transposase-Assisted ChIP
(TAM-ChIP), a novel method that enables antibody directed insertion of Next Generation
Sequencing adapters and antibody specific barcodes directly into cross-linked chromatin.
In addition to eliminating the library preparation step, this assay has the potential to
significantly reduce the required input chromatin amount, and to eliminate the chromatin
shearing and immunoprecipitation steps of the traditional ChIP assay.
This innovative transposase-based ChIP technology will allow streamlining of the
genome-wide analysis of histone marks and transcription factors through antibody
directed insertion of barcodes. Combined with the prospective of multiplexing various
targets within the same sample, and the low chromatin input requirements, this method
has the potential to revolutionize ChIP-seq.
SPEAKER ABSTRACTS
39
Invited Talk
Pedro Medina
Genyo, Granada, Spain
MicroRNAs, Chromatin Remodeling complexes and cancer.
SWI/SNF chromatin-remodeling complex, which alters the interactions between DNA
and histones and modifies the availability of the DNA for transcription. The latest deep
sequencing of tumor genomes has reinforced the important and ubiquitous tumor
suppressor role of the SWI/SNF complex in cancer. However, although SWI/SNF
complex plays a key role in gene expression, the regulation of this complex itself is
poorly understood. SMARCA4 is the catalytic subunit of the SWI/SNF complex and it has
chromating-remodelling activity by itself. Significantly, an understanding of the regulation
of SMARCA4 expression has gained in importance due to recent proposals incorporating
it in therapeutic strategies that use synthetic lethal interactions involving several SWI/SNF
subunits.
We have observed that the loss of expression of SMARCA4 observed in some primary
lung tumors, whose mechanism was largely unknown, can be explained, at least partially
by the activity of microRNAs (miRNAs). We observed that SMARCA4 expression is
regulated by miR-101, miR-199 and especially miR-155 through their binding to two
alternative 3’UTRs. These experiments suggest that the oncogenic properties of miR-155
in lung cancer can be largely explained by its role inhibiting SMARCA4. This functional
relationship could explain the poor prognosis displayed by patients that independently
have high miR-155 and low SMARCA4 expression levels. In addition, these results could
lead to application of incipient miRNA technology to the aforementioned synthetic lethal
therapeutic strategies.
SPEAKER ABSTRACTS
41
Invited Talk
Eduardo Eyras
Pompeu Fabra University and ICREA, Barcelona, Spain
RNA processing alterations as drivers and prognostic markers of
cancer
Alterations in RNA processing are emerging as important signatures to understand tumor
formation and to develop new therapeutic strategies. However, it is not yet known the
extent to which these alterations can be considered drivers or whether specific patterns
of RNA processing can be predictive of prognosis. We describe our efforts to determine
the functional impact and relevance in cancer of RNA processing alterations measured
in 11 cancer types. We describe potential RNA-based drivers and markers of tumor
stage and survival. These novel signatures expand the catalogue of candidate actionable
alterations in tumors and potentially complement current strategies in precision cancer
medicine.
SPEAKER ABSTRACTS
43
Invited Talk
Carlo M. Croce
The John W. Wolfe Chair in Human Cancer Genetics, Department of Molecular Virology,
Immunology and Medical Genetics, Director, Genetics Institute, The Ohio State University
Medical Center
Causes and consequences of microRNA dysregulation in cancer
Since the discovery of miR-15a and miR-16-1 deletions in CLL, many laboratories
around the world have shown miRNA dysregulation in all tumors studied, including
the most common, such as lung, breast, prostate and gastrointestinal cancers. Such
dysregulation, like the dysregulation of oncogenes and tumor suppressor genes, can be
caused by multiple mechanisms, such as deletion, amplification, mutation, transcriptional
dysregulation and epigenetic changes.
As miRNAs have multiple targets, their function in tumorigenesis could be due to their
regulation of a few specific targets, possibly even one, or many targets. A future challenge
will be to identify all of the targets of the miRNAs involved in cancer and establish their
contribution to malignant transformation. An additional challenge will be the identification
of all of the miRNAs that are dysregulated by pathways that are consistently dysregulated
in various types of human cancers. This point is of particular importance, as instead of
focusing on specific alterations in protein-coding oncogenes or tumor suppressor genes
— which may be difficult to treat — we could focus on their downstream miRNA targets.
If these miRNA targets are crucial for the expression of the malignant phenotype and the
cancer cells depend on their dysregulation for proliferation and survival, we can expect
that the use of miRNAs or anti-miRNAs will result in tumor regression. Genomic analyses
for alteration in miRNA genes or for copy number alterations in various human tumors by
deep sequencing is in progress but has not been completed. These studies could provide
additional information concerning the involvements of miRNAs in cancer and in many
other diseases.
Over the past few years, we have observed a shift from conventional chemotherapy to
targeted therapies, and miRNAs and anti-miRNAs will contribute extensively to the latter.
SPEAKER ABSTRACTS
45
Invited Talk
Aleix Prat
Medical Oncology Department, Hospital Clínic, University of Barcelona, Spain
Clinical implications of the intrinsic molecular subtypes
Gene-expression profiling has had a considerable impact on our understanding of breast
cancer biology. During the last 15 years (yrs), 5 intrinsic molecular subtypes of breast
cancer (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) and a normal
breast-like group have been identified and intensively studied. In this presentation, I
will focus on recent data regarding the potential clinical implications of the intrinsic
molecular subtypes beyond the current pathological-based classification. Within hormone
receptor (HR)-positive and HER2-negative breast cancer, the Luminal A and B subtypes
represent the vast majority of cases. Compared to Luminal A tumours, Luminal B tumours
are characterized by higher expression of proliferation/cell cycle-related genes and
lower expression of several luminal-related genes such as the progesterone receptor.
Clinically, Luminal B tumours show higher pathological complete response rates following
neoadjuvant multi-agent chemotherapy but worse distant recurrence-free survival at
5- and 10-yrs regardless of adjuvant systemic therapy compared to Luminal A tumours.
Within clinically HER2+ disease, all the 4 main intrinsic subtypes can be identified beyond
HR status, albeit with different proportions. Among them, the HER2-enriched subtype
represents the majority of HER2+ tumours and shows higher expression of HER2 and
lower expression of luminal genes compared to both luminal subtypes. In addition,
retrospective data suggests that patients with HER2-enriched disease benefit the most
from neoadjuvant trastuzumab, or dual HER2 blockade with trastuzumab/lapatinib, in
combination with chemotherapy. Of note, once intrinsic subtype is taken into account,
the biological impact and the prognostic ability of clinical HER2 disappears. Finally, within
triple-negative breast cancer (TNBC), the Basal-like disease predominates (70-80%), but
again, all the intrinsic subtypes can also be identified. Importantly, the distinction between
Basal-like versus non-Basal-like within TNBC seems to be important for predicting
survival following (neo)adjvuvant multi-agent chemotherapy, bevacizumab benefit in the
neoadjuvant setting, and docetaxel vs. carboplatin benefit in first-line metastatic disease
(TNT study). Overall, this data suggests that intrinsic molecular profiling provides clinically
relevant information beyond current pathology-based classifications
SPEAKER ABSTRACTS
47
Invited Talk
Egbert Smit
Egbert F. Smit MD PhD. Department of Thoracic Oncology, Netherlands Cancer Institute and
Department of Pulmonary Diseases, Vrije Universiteit VU Medical Center, Amsterdam, The
Netherlands.
Molecular imaging using radiolabeled drugs in lung cancer
Background: Anticancer drugs can be labeled with positron emitters to study in vivo
pharmacokinetics. The development of radiolabeled anticancer drugs will be illustrated
by studies of carbon-11 labeled docetaxel ([11C]docetaxel) and [11C]-erlotinib in lung
cancer patients.
Methods and Results: Biodistribution and actual human radiation dosimetry of [11C]
docetaxel was determined in 7 patients with solid tumors (van der Veldt et al., 2010).
The effective dose of [11C]docetaxel was 4.7µSv·MBq−1, comparable to the estimated
effective dose in rats. [11C]docetaxel showed low uptake in human lungs., and therefore
could be a useful tracer for tumors in the thoracic region.
Tumor kinetics of [11C]docetaxel were irreversible and could be quantified using Patlak
graphical analysis. In tumors, the net rate of influx (Ki) of [11C]docetaxel was variable
and strongly related to tumor perfusion,. Also, dexamethasone pretreatment significantly
lowered 11C-Docetaxel uptake in human tumors.
The microdosing concept was subsequently validated. (van der Veldt et al., 2013).
Docetaxel naive lung cancer patients underwent two [11C]docetaxel PET scans, one after
a bolus injection of a tracer dose [11C]docetaxel and another during a combined infusion
of [11C]docetaxel and docetaxel (75mg·m−2). The accumulated amount of docetaxel in
tumors was <1% of the total infused dose of docetaxel (van der Veldt et al. 2013).
For 11C-erlotinib a microdosing study has been performed in advanced EGFR WT and
EGFR mutated NSCLC patients. We were able to show a significant difference in volume
of distribution between these patients, where in EGFR mutated patients significant higher
tumor uptake was observed. Next, this methodology was applied to difficult clinical cases
in order to better predict tumor responses following treatment with EGFR tki.
Conclusion: PET using radiolabeled anticancer drugs enables assessment of
accumulation of drugs in human tumors and may facilitate rational treatment choices that
are tailored to improve drug delivery to tumors.
SPEAKER ABSTRACTS
49
Invited Talk
Robert Torka
Authors: Robert Torka, Kinga Pénzes, Christine Baumann and Axel Ullrich
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried,
Germany
Compensatory mechanisms to AXL Receptor Tyrosine Kinase
Inhibitors
The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for
targeted therapy of cancer. However, the benefits of targeted therapies are limited due
to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer
cells are able to overcome targeted Axl therapies. We were able to identify several
compensation mechanisms to Axl inhibitors. Here, we demonstrate that inhibition of
Axl by siRNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression
of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)–
dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Inhibition of
cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3,
suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111
simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback
activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and
lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and
Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue
origin indicated a low basal phosphorylation of RAC-α serine/threonine-protein kinase
(AKT) as a general requirement for HER3 activation upon Axl inhibition. On the contrary
we could demonstrate that cancer cell lines with high basal AKT phosphorylation status,
e.g. Hs578T or SKOV3, respond to Axl inhibition using BMS777607 or MPCD84111
by up regulation of Axl expression and enhanced Axl phosphorylation levels within
24-48 hours post treatment. Therefore, we conclude that, only in patient cohorts with
expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3
kinase would be beneficial to overcome the compensation mechanism to Axl-targeted
therapies. Consequently, phosphorylation of AKT arises as an independent biomarker
for Axl treatment and we introduce the phosphorylation of HER3 as an independent
pharmacodynamic biomarker for monitoring of anti-Axl therapy response.
SPEAKER ABSTRACTS
51
Invited talk
Takashi Kohno
National Cancer Center Research Institute (NCCRI), Tokyo, Japan
RET fusion and chromatin remodeling genes: targets for precision
lung cancer medicine
About half of lung adenocarcinomas develop through activation of the EGFR, KRAS
or ALK oncogene in Japan and other Asian countries. EGFR and ALK tyrosine kinase
inhibitors (TKIs) show a high therapeutic effect against lung adenocarcinomas carrying
EGFR mutations or ALK fusions. We and others identified the RET fusion gene present in
1-2% of lung adenocarcinomas as a new therapeutic target (1, 2). A phase II investigatorinitiated clinical trial of a RET TKI, vandetanib, in patients with RET fusion-positive lung
cancer [Principal investigator: Koichi Goto of the National Cancer Center Hospital East]
was commenced at the beginning of 2013. For the purpose, a Nation-wide screening
of RET fusion positive lung cancer, designated LC-SCRUM, involving >190 hospitals
in all 47 prefectures, is currently in progress. Up to the present, >1500 patients have
been screened and > 30 RET fusion-positive cases have been identified. In lung
adenocarcinoma, other oncogene aberrations, such as ROS1 fusion, NRG1 fusion, and
BRAF mutation, have been identified as therapeutic targets (2, 3).
On the other hand, we revealed that, lung adenocarcinomas negative for the oncogene
aberrations above, inactivation of chromatin-regulating genes, such as SMARCA4/
BRG1, is frequent. We propose a new therapeutic method for SMARCA4/BRG1-deficient
cancers based on inhibiting SMARCA2/BRM ATPase, a paralogous protein of SMARCA4/
BRG1 (4).
Multiplex gene testing of surgery or biopsy samples is necessary to facilitate personalized
molecular-targeted therapy of lung adenocarcinoma. A feasibility study conducted in the
National Cancer Center will be introduced and discussed.
1.
2.
3.
4.
Kohno T et al, Nat Med, 2012
Kohno T et al, Transl Lung Cancer Res, 2015
Nakaoku T et al, Clin Cancer Res, 2014
Oike T et al, Cancer Res, 2013
SPEAKER ABSTRACTS
53
Rafael Rosell
Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital
Germans Trias i Pujol, Badalona, Barcelona, Spain
Germans Trias i Pujol Health Science Research Institute and Hospital, Campus Can Ruti,
Badalona, Barcelona, Spain, Molecular Oncology Research (MORe) Foundation, Barcelona,
Spain
Bypass Tracks in Lung Cancer Resistance
There is a need to improve survival of lung cancer patients with EGFR mutations
stemming from growing evidence that, following EGFR TKI inhibition, STAT3 activation
occurs almost immediately, a few hours after exposure to gefitinib or erlotinib and
gradually increases. The mechanisms of STAT3 activation were identified through IL-6/
JAK1/STAT3 and also more recent evidence shows that erlotinib can directly induce
pSTAT3 (Tyr705) by dephosphorylating PTPMeg2. Combinations of gefitinib or erlotinib
with repurposed drugs such as metformin and niclosamide prevent and reverse TKI
resistance in xenograft models. We were able to identify high levels of BIM mRNA
expression as a predictive marker of response, PFS and OS in erlotinib-treated NSCLC
patients. We posit that one third of EGFR mutant NSCLC patients expressing high BIM
mRNA could be related to low SHP2 and these patients are prompted to have rapid or
immediate pSTAT3 phosphorylation and gradual elevation of STAT3 at transcriptional
level. EGFR mutant cell lines show low levels of SHP2 which attenuates ERK signaling
and therefore preserves BIM from proteosomal degradation. At the same time, SHP2
is a negative regulator of STAT3 signaling. For more than 50% of EGFR mutant NSCLC
patients with low/intermediate BIM mRNA expression we found that response rate was
significantly lower (less than 40%) with shorter PFS and OS. We speculate that in this
significant subgroup of patients, other RTKs can be activated such as EPHA2, AXL/MER
which upregulate SHP2 and STAT3. We are investigating which of these RTKIs could be
most significant to cause intrinsic resistance with low BIM mRNA expression and several
synthetic lethal approaches.
SPEAKER ABSTRACTS
55
Invited Talk
Webster K. Cavenee
Ludwig Institute for Cancer Research, UC San Diego
A novel “hide and seek” mechanism driving therapeutic resistance
Intratumoral genetic heterogeneity contributes to cancer drug resistance but the
underlying mechanisms are poorly understood. We used single cell analyses of patientderived cell cultures, xenografts and tissue from glioblastoma patients to make the
surprising observation that tumor cells reversibly upregulate or suppress oncogene
expression, conferring distinct cellular phenotypes to reach an optimal equilibrium
for growth. Acquired resistance to EGFR tyrosine kinase inhibitor (TKI) is mediated by
elimination of EGFR from extrachromosomal DNA. After drug withdrawal, re-emergence
of clonal EGFR mutations on extrachromosomal DNA follows. These results demonstrate
a highly specific, dynamic, and adaptive means by which cancers can evade targeted
therapies directed at oncogenic drivers carried on extrachromosomal DNA.
SPEAKER ABSTRACTS
57
Poster 1
Hakan Akca
Hakan Akaca (presenting author)
Hakan Akca1, Sakir Akgun1, Hakan Kucuksayan1, Onur Tokgun1, Aydin Demiray1, Ege R.
Karagur1 1Pamukkale University, School of Medicine, Medical Biology Depertment, Denizli/
Turkey
NFkB mediated induction of miRNA genes expression is responsible
for NSCLC invasion
NFkB mediated induction of miRNA genes expression is responsible for NSCLC invasion
Hakan AKCA1, Sakir Akgun1, Hakan Kucuksayan1, Onur Tokgun1, Aydin Demiray1, Ege
R. Karagur1 1Pamukkale University, School of Medicine, Medical Biology Depertment,
Denizli/Turkey Lung Cancer is the leading cause of cancer relited deaths in the world
and approximetly 90% patients with lung cancer ultimately die from metastatic disease.
Metastasis is the most dangerously step of cancer. In our recently published work
showed that Akt/NFKB pathway is continously active and induces cellular invasion and
PTEN suppresses cellular invasion via inhibition of Akt/NFKB pathway. In this study
we aimed to show NFKB mediated induction of miRNA expression can responsible
for inducing NSCLC invasion. We used miRNA Chip Sequencing for detection of TNF
induced NFKB mediated miRNA expression. Our Chip-seq results indicate that NFKB
binds several miRNA promoter and induction of these miRNA expression which on
potantially regulating NFKB relited NSCLC invasion.
This study supported by TUBITAK grant number 112S636
POSTER ABSTRACTS
Poster 2
Sakir Akgun
Sakir Akgun(1), Hakan Kucuksayan(1), Ege Riza Karagur(1), Aydin Demiray(1), Hakan Akca(1)
(1) Pamukkale University School of Medicine Medical Biology Depertmant, Turkey
The inhibitory effects of several NFkB specific inhibitors on NFkB
actvity and cellular invasion on PC3, PC14 and H1299 NSCLC cell
lines.
Metastasis is the most dangerous event of cancer and invasion, a critical step of
metastasis can induced by several pathway and molecules. In our previously study,
we demonstrated that PI3K/AKT/NFkB pathway is constantly active in non-small cell
lung cancer which has more invasive character in cancer. Therefore, the inhibition of
PI3K/AKT/NFkB pathway can regulate invasion ability of NSCLC cells. In this study
we want to examined the potential specific NFkB inhibitors and their inhibition activity
on TNF? induced NFkB activity through NSCLC cell invasion. We used specific NFkB
inhibitors such as BAY11-7082, MG132, LY294002, Triptolide for specifically inhibit NFkB
activity. NFkB activity measured by Luciferase Assay and EMSA method, invasion was
determined with BD invasion chamber. Our result indicated that among specific NFkB
inhibitors BAY11-7082, MG132, LY294002, Triptolide only BAY11-7082 can specificly
inhibit TNF? related inhibtion of NFKB transcriptional and DNA binding activity of cellular
invasion on H1299, PC3, PC14 NSCLC cell lines.
This study is supported by TUBİTAK grant number 112S63
59
Poster 3
Laura Bonanno
Laura Bonanno (presenting author) 1, Elisabetta Zulato 2, Angela De Paoli 3, Fiorella
Calabrese 4, Giovanni Esposito 2, Alessandro Del Conte 5, Francesco Oniga6, Elisabetta Di
Liso 1, Pierfranco Conte 1, Adolfo Favaretto 1, Stefano Indraccolo 2.
1. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Via Gattamelata 64, Padova
(IT) 2. Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Via
Gattamelata 64, Padova (IT) 3. Clinical Trials and Biostatistics Unit, Istituto Oncologico
Veneto-IRCCS, Via Gattamelata 64, 35138 Padova, Italy; 4. Department of Pathology
and Cytology, Università degli Studi di Padova, Via Giustiniani 2, Padova (IT) 5. Medical
Oncology, Azienda Ospedaliera Santa Maria degli Angeli, Via Mon
Markers of glycolytic phenotype and outcome in platinum-treated
advanced Non-small cell lung cancers (NSCLCs)
Background: The mainstay of treatment of non oncogene-addicted advanced NSCLCs
is platinum-based chemotherapy and the median overall survival (OS) is inferior to one
year. No molecular predictive/prognostic markers are clinically available. Changes in cell
metabolism represent one of the hallmarks of cancer. Many tumors predominantly rely
on glycolysis for energy production, instead of mitochondrial oxidation. The metabolic
phenotype could influence tumor natural history and/or response to chemotherapyinduced cellular stress. Methods: We retrospectively selected 106 advanced
NSCLCs patients treated with first-line platinum-based chemotherapy. We used
immunohistochemistry for examining the protein expression of Kinase Liver B1 (LKB1),
a main regulator of cell metabolism, and of monocarboxylate transporter 4 (MCT4),
a trans-membrane transporter of lactate. We analyzed the effect of the markers,
considered as categorical variables, on OS, progression-free survival (PFS) and
radiological response. Results: The median OS and PFS of the study population were
10.3 (95%IC: 8.3-13.5) and 6.7 (95%IC: 5.6-7.2) months, respectively. The response
rate was 39.8%. LKB1 and MCT4 expression was not statistically associated with
response rate and PFS. Among patients surviving more than 3 months (n=56 with IHC
results available), the risk of death was significantly higher in the presence of high
levels (scores>6) of MCT4 (HR: 2.1. 95% IC: 1.3-4.1; p: 0.0237) compared to MCT4
scores?6. When categorizing the expression levels of MCT4 into 3 strata, we identified
three groups of patients with different outcome: patients expressing high levels of MCT4
(scores?15) achieved a median OS of 6.6 (95%IC: 3.7-12.6) months, whereas the median
OS was 9.5 (95%IC: 5.7-13.5) and 17.4 (95%IC: 4.9-nd), when MCT4 was intermediate
or null, respectively (p: 0.0317). Conclusions: MCT4 expression could affect prognosis
of platinum-treated advanced NSCLCs, suggesting that characterization of metabolic
traits could pave the way to new therapeutic perspectives. Further study on metabolic
phenotype and correlation to genetic characterization has been planned.
POSTER ABSTRACTS
Poster 4
Ester Bonastre Llort
Ester Bonastre(1) (presenting author), Sara Verdura(1), Ilse Zondervan(2), Federica
Facchinetti(3), Sylvie Lantuejoul(4), Maria Dolores Chiara(5), Juan Pablo Rodrigo(5), Julian
Carretero(6), Enric Condom(7), Agustin Vidal(7), David Sidransky(8), Alberto Villanueva(9),
Luca Roz(3), Elisabeth Brambilla(4), Suvi Savola(2), Montse Sanchez-Cespedes(1). (1)Bellvitge Biomedical Research Institute, Spain. (2)MRC-Holland, The Netherlands. (3)
Fondazione IRCCS Istituto Nazionale Tumori, Italy. (4)University Joseph Fourier, France. (5)
Hospital Universitario Central de Asturias, Spain. (6)University of Valencia, Spain. (7)Bellvitge
Hospital, Spain. (8)Johns Hopkins University School of Medicine, USA. (9)Catalan Institute of
Oncology, Spain.
PARD3 inactivation in lung squamous cell carcinomas impairs STAT3
and promotes malignant invasion.
Correct apicobasal polarization and intercellular adhesions are essential for the
appropriate development of normal epithelia. Here, we investigated the contribution of
the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas
(LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCC examined placing
PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3
mutant proteins exhibited a relative reduction in the ability to mediate formation of tight
junctions and actin-based protrusions, bind aPKC, activate RAC1 and activate STAT3 at
cell confluence. Thus, PARD3 alterations prevented the formation of contacts between
neighboring cells and the subsequent downstream signaling. Notably, reconstituting
PAR3 activity in vivo reduced tumor invasive and metastatic properties. Our findings
define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that impacts
tumor aggressiveness and metastasis.
61
Poster 5
Raquel Buj
(Raquel Buj1), Izaskun Mallona1, Anna Díez-Villanueva1, Veronika Mancikova2, Esmeralda
Castelblanco3, Mar Muñoz1, Dídac Mauricio4, Manel Puig-Domingo5, Xavier MatiasGuiu6, Francisco Xavier Maravall3, Mercedes Robledo2, Jordi Lluis Reverter5, Mireia
Jordà1, Miquel A. Peinado1
1: Institute of Predictive and Personalized Medicine of Cancer (IMPPC) 2: Hereditary
Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO) 3: Department
of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, IRBLLEIDA 4:
Department of Endocrinology and Nutrition, University Hospital Germans Trias i Pujol 5:
Germans Trias i Pujol Health Sciences Research Institute (IGTP) 6: Department of Pathology,
University Hospital Arnau de Vilanova, University of Lleida,
Quantification of Unmethylated Alu repeats (QUAlu): a new cost
effective clinical tool to assess global hypomethylation in human
cancer
It is well known that loss of global DNA methylation is a hallmark of most cancers.
Numerous works have demonstrated that DNA hypomethylation is an early and
maintained event in tumorigenesis, and more importantly, that the degree of DNA
hypomethylation is strongly associated with the tumor stage. Therefore, it has attracted
great interest for its clinical value not only as a diagnostic biomarker but also as a
marker to predict cancer prognosis. Nowadays there are a wide variety of techniques to
assess global DNA methylation: high performance separation means, digestion of DNA
with methylation-sensitive and -insensitive restriction enzymes, bisulphite conversion
etc. Several of these approaches use a surrogate reporter like transposable elements,
which exhibit a high copy number and are widespread throughout the human genome.
However none of these methods have been established in the clinical practice due to
their technical, economical and time requirements. Here we present a new technique
for Quantification of Unmethylated Alu elements (QUAlu) that can be applied to samples
routinely obtained for pathological examination (fresh tissue, stools, blood, FNABs,
etc), even when DNA is partially degraded. QUAlu performance has been evaluated for
reproducibility and accuracy. We have applied it to analyze Alu repeat demethylation in a
large series of lung, colon, breast, prostate and thyroid carcinomas as well as their paired
normal tissues. Our results reveal that lung and colon carcinomas are higher and more
frequently hypomethylated than breast, prostate and thyroid tumors. Interestingly, we
have found differences between lung adenocarcinoma and squamous cell carcinoma.
Furthermore, there is an increasing trend in lung tumors to become hypomethylated from
former to current smokers. Finally, there are not differences in the methylation degree of Alu
elements among the analyzed normal tissues. In summary, QUAlu appears as a specific,
cheap and simple technique that can enhance the diagnostics and prognostics of cancer.
POSTER ABSTRACTS
Poster 6
Eva Capdevila-Busquets
Eva Capdevila-Busquets1,2, Rodrigo Arroyo1,2, Montse Soler-López1,2, Patrick Aloy1,2,
1 Structural Bioinformatics and Network Biology Group. Institute for Research in
Biomedicine. Barcelona.
2 Joint IRB-BSC Research Program on Computational Biology, Institute for Research in
Biomedicine. Barcelona.
3 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona.
Breast Cancer Genes PSMC3IP and EPSTI1 Play a Role in Apoptosis
Regulation
Breast cancer is the second most frequently diagnosed cancer in women, with one million
of new cases every year worldwide. The balance between proliferation and apoptosis
is crucial in determining the overall growth or regression of the tumor in response to
chemotherapy, radiotherapy and hormonal treatments. Thus, it is possible to delineate
the biology of individual tumors at the molecular and biochemical level by examining
apoptosis and its control and regulation, and to exploit these to clinical advantage. To this
end, we have selected genes potentially involved in apoptosis based on a breast cancer
protein network analysis carried out in our group (Arroyo et al. submitted). We have
induced or inhibited our candidate genes in different human breast cancer cell lines by
means of overexpression or gene silencing experiments, respectively, and subsequently
applied apoptotic assays to evaluate the role of these genes in apoptosis in the context
of breast cancer. Our preliminary findings suggest a new antiapoptotic role for two breast
cancer associated genes. Further experiments are required to clearly elucidate the
potential therapeutical applications of these genes in breast cancer treatments.
63
Poster 7
Imane Chaib
Imane Chaib-1 (Presenting author), Belen Sànchez-1, Maria Perez Cano-1, Montserrat
Tierno-1, Jose Luis Ramirez-1, Ana Drozdowskyj-2, Carles Codony-3, Jordi Codony-3, Niki
Karachaliou-4, Teresa Moran-1, Enric Carcereny-1, Rafael Rosell-1,
1-Catalan Institute of Oncology, Badalona, Barcelona, Spain; 2-Pivotal, Madrid, Spain;
3-Pangaea Biotech SL, Barcelona, Spain; 4-Dr Rosell Oncology Institute, Quirón Dexeus
University Hospital, Barcelona, Spain
BIM and SHP2 expression levels predict clinical outcome to EGFR
tyrosine kinase inhibitors (TKI) in EGFR-mutant non-small-cell lung
cancer (NSCLC) patients
Background: EGFR mutations are among the most common driver mutations,
responding well, albeit transiently, to EGFR TKIs. We were able to identify high levels
of BIM mRNA expression as a predictive marker of response, progression free survival
(PFS) and overall survival (OS) in erlotinib-treated NSCLC patients. The Src-homology 2
domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is downstream of both
EGFR and several other receptor tyrosine kinases (RTK). SHP2 is required for sustained
activation of extracellular signal-regulated kinase (ERK) and BIM downregulation.
Methods: We assessed the static levels of BIM and SHP2 mRNA expression, by
quantitative real time polymerase chain reaction, and correlated our findings with PFS
and OS in 30 EGFR-mutant NSCLC patients treated with EGFR TKIs like erlotinib,
gefitinib or afatinib.
Results: Median age 68; 73.3% female; 73.3% never-smokers; 83.3% adenocarcinoma;
80% erlotinib treated; 66.7% response rate to EGFR TKIs. PFS was 22.3 months (m) for
patients with intermediate/high BIM compared to 10.7 m for patients with low BIM mRNA
expression levels (P=0.007). No significant differences in PFS were observed according to
the expression levels of SHP2. Notably, PFS was 28.8 m for patients with both low SHP2
and intermediate/high BIM mRNA expression compared to 7.3 m for p with high SHP2
and low BIM expression (P=0.0082). No significant differences in OS were observed
according to the expression levels of the two genes.
Conclusions: Therapeutic decisions based solely on mutational biomarkers could
have limited benefit. Our findings reinforce the usefulness of BIM mRNA as a predictive
biomarker for the outcome to EGFR TKIs therapy. The non-transmembrane protein
tyrosine phosphatase SHP2 plays an essential role in most, if not all, RTK signaling
pathways activating ERK and downregulating BIM. Patients with low BIM and high SHP2
expression could derive only a meager benefit from treatment with EGFR TKIs alone but
could benefit from synthetic lethality combinations.
POSTER ABSTRACTS
Poster 8
Aydin Demiray
Aydin Demiray (presenting author), Hakan Akca
Pamukkale University school of medicine Medical Biology department
Updated frequency of EGFR and KRAS mutations in non-small cell
lung cancer (NSCLC) in TURKEY and response to erlotinib
Mutations in the EGFR gene are critical determinants of treatment with EGFR tyrosine
kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) patients. DNA was isolated
from the formalin-fixed, paraffin- embedded 200 Turkish NSCLC patients and their EGFR
mutation status was examined by pyrosequencing. EGFR mutations were detected in 72
of the 200 patients (36%); 29 patients with delE746-A750, 15 patients with L861Q, 10
patients with L747-T751 ins P, 8 patients with L858R, 8 patients with G719A, 3 patients
withT790M, 3 patients with G712S, 2 patients with delE746-T751 ins I, 1 patients with
delE746-A750 IP, 1 patients with delL747-P753 S and 1 patients with G719C. KRAS
mutations were detected in 43 of the 200 patients (21.5%); 10 patients with G12S, 8
patients with G12C, 6 patients with G12D, 3 patients with G12V, 10 patients with Q61H,
7 patients with Q61R and 1 patients with G12A. Sixteen patients with EGFR and KRAS
mutations were detected.
EGFR mutations were associated with gender (51% in females vs. 31.9% in males; p<
0.001), non-smoker status (51.6% vs 31.1%; p< 0.001), adenocarcinoma (37.8%ad
vs 26.8%) and the KRAS mutation were associated with patients age (27.5% <62 vs
13.4% 62> p< 0.001). EGFR mutations was EGFR mutation status objective response to
erlotinib (P<0.05). Over-all survival time was significantly longer in the patients with EGFR
mutations than in the patients without EGFR mutations (146 vs 84 week, 0=0,020)
65
Poster 9
Gabrijela Dumbovic
Gabrijela Dumbovic1 (presenting author), Johanna Samuelsson2,3, Sergio Alonso1,2,
Sonia Forcales1, Manuel Perucho1,2
(1) Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain
(2) Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA (3) Active
Motif, Carlsbad, California, USA
Chromatin Organization and Transcriptional Regulation of a
Pericentromeric Repetitive Element in Colorectal Cancer
We identified a frequently hypomethylated genomic region in colorectal tumors that
belongs to the family of a moderately repetitive pericentromeric element called SST1.
15% of the tumors analyzed exhibited an age-dependent demethylation that follows
our ?wear & tear? model linking aging with cancer through gradual demethylation.
However, 7% of the patients displayed a more severe age-independent demethylation.
Methylated SST1 shows low H3K27me3 and high H3K9me3 levels, while demethylated
SST1 co-occurs with an increase of H3K27me3, lower levels of H3K9me3 and
increased transcription. This upregulated SST1 transcription in the presence of an
increased polycomb-repressive mark (H3K27me3) was puzzling. To gain insight on
the mechanisms underlying this peculiar transcription, a DNA demethylation treatment
with 5-aza-2’-deoxycytidine (AZA) was performed in combination with the inhibition
of the PRC2 complex (GSK126). In the absence of a functional PRC2, the expression
of SST1 elements was higher than in cells treated only with AZA. However, when AZA
treatment was followed by Trichostatin A (TSA), which inhibits histone deacetylases,
SST1 expression was much more increased. This epigenetic reprogramming also occurs
in ovary and breast cancer cell lines and importantly in primary colorectal tumors.
Further characterization of the RNA originating from SST1 elements shows that it is
predominantly non-polyA, transcribed by RNA polymerase II and it is mainly associated
to the chromatin, which reinforces a non-coding role. The results gathered in this study
indicate that DNA methylation and histone deacetylation contribute to the silencing of the
SST1 elements in different tissues. Our hypothesis is that upon demethylation in cancer
(by a yet unidentified mechanism), the SST1 elements acquire the polycomb repressive
mark H3K27me3 in an attempt to maintain the region silenced. However, this mechanism
cannot fully repress SST1 expression as DNA methylation does. Further disruption of
histone deacetylation at hypomethylated SST1 region in normal colon epithelium could
lead to aberrant overexpression of SST1 elements, with yet unknown consequences.
POSTER ABSTRACTS
Poster 10
Miquel Duran-Frigola
Miquel Duran-Frigola (1) (presenting author), David Rossell (2,3), Patrick Aloy (1,4)
(1) Joint IRB-BSC-CRG Program in Computational Biology, Spain (2) Biostatistics and
Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), Spain (3)
Department of Statistics, University of Warwick, UK (4) Institució Catalana de Recerca i
Estudis Avançats (ICREA), Spain
A chemo-centric view of human health and disease
Efforts to compile the phenotypic effects of drugs and environmental chemicals offer
the opportunity to adopt a chemo-centric view of human health that does not require
detailed mechanistic information. Here we consider thousands of chemicals and analyse
the relationship of their structures with adverse and therapeutic responses. Our study
includes molecules related to the aetiology of 934 health-threatening conditions and used
to treat 835 diseases. We first identify chemical moieties that could be independently
associated with each phenotypic effect. Using these fragments, we build accurate
predictors for approximately 400 clinical phenotypes, finding many privileged and liable
structures. Finally, we connect two diseases if they relate to similar chemical structures.
The resulting networks of human conditions are able to predict disease comorbidities, as
well as identifying potential drug side effects and opportunities for drug repositioning, and
show a remarkable coincidence with clinical observations.
67
Poster 11
Francesco Paolo Fiorentino
Francesco Paolo Fiorentino (1), Sabrina Giampaolo (1,2), Takashi Kohno (3), Laura Soucek
(4,5), Jun Yokota (1,3)
(1) Genome Biology Group, Institute of Predictive and Personalized Medicine of Cancer
(IMPPC), Barcelona, Spain (2) Department of Biosciences, University of Parma, Parma, Italy
(3) Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
(4) Vall d’Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d’Hebron,
Barcelona, Spain (5) Catalan Institution for Research and Advanced Studies (ICREA
Effectiveness of MYC Inhibition in Suppressing the Growth of Small
Cell lung Cancer Cells Carrying TP53 and RB1 Mutations
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with high
mortality, characterized by early metastasis and resistance to chemotherapies after
disease recurrence. Therefore, it is a very important issue to develop a novel strategy of
treating SCLC patients for the improvement of their outcomes. Both the TP53 and RB1
genes are genetically inactivated in almost 100%, and the MYC family genes, MYC,
MYCL1 and MYCN, are amplified in ~20% of SCLC cases. Since c-Myc, L-Myc, or
N-Myc protein is overexpressed in SCLC cells with amplification of the respective MYC
family gene, we hypothesized that Myc family proteins could be valuable targets for the
therapy of SCLC patients. However, it has been suggested that inactivation of TP53 and/
or RB1 could interfere with the therapeutic approaches based on Myc targeting. Myc
family proteins are transcription factors that require the heterodimerization with Max
to bind DNA and drive transcription of numerous target genes. To assess the potential
of MYC family genes as a target of therapy in SCLC, we used Omomyc, a dominant
negative form of c-Myc that prevents the heterodimerization of Myc family proteins with
Max and examined the effects of Myc inhibition in a panel of SCLC cell lines carrying
amplified MYC family genes in addition to genetic inactivation of the TP53 and RB1
genes. Induction of Omomyc expression suppressed the growth in all MYC, MYCL1 or
MYCN amplified SCLC cell lines. Growth suppression was caused by induction of G1
arrest and/or apoptosis. Furthermore, induction of G1 arrest by Omomyc was found to
be dependent on the activation of p21. These results indicate that modulation of p21
expression by Myc proteins plays a fundamental role on the proliferation of SCLC cells
and Myc targeting will be an effective approach to suppress the growth of SCLC cells.
POSTER ABSTRACTS
Poster 12
Silvia Garcia Roman
García-Roman, S. (1), Molina Vila, M.A. (1),R., Borrell Bilbao, J.I. (2), Puig de la Bellacasa
Cazorla, R. (2), Morales Espinosa, D. (3), Bertràn Alamillo, J. (1), Gimenez Capitàn, A. (1),
Karachaliou, N. (1), Rosell, R. (1)
(1)Pangaea Biotech, Barcelona, Spain (2)Instituto Químico de Sarrià (IQS), Barcelona, Spain
(3)Instituto Oncológico Rosell, Hospital Universitario Quirón-Dexeus, Barcelona, Spain
PB1 a new DDR2 inhibitor: Potential treatment to SCC patients
Introduction: Discoidin domain receptor 2 (DDR2) is a recently identified oncogenic driver
kinase in squamous cell carcinoma of the lung. It is a receptor tyrosine kinase activated
by several collagen ligands and involved in tumor progression of lung squamous cancer
cells (SCC) (1). Recent exon sequencing studies have identified DDR2 to be mutated
in 3% to 4% of lung SCC (2). DDR2 is also a receptor expressed during epithelialmesenchymal transition (EMT) (3) and it is an upstream activator of SHP2 that, in turn, is
a key signaling node which leads to activation of multiple signaling pathways (4). PB1,
a DDR2 inhibitor has emerged as a new therapeutic option Results and discussion: Due
to enzymatic assays of PB1, DDR2 has emerged as a possible target. Different cell lines
carrying DDR2 mutations (L239R and I638F) are sensitive to the compound with an IC50
in the nanomolar range. Next, the effect of PB1 in FBS-induced phosphorylation of the
DDR2 receptor was tested in H2286 cells. H2286 is a lung SCC cell line with I638F DDR2
mutation where PB1 at 0.1 µM significantly inhibited DDR2 phosphorylation. In different
KRAS-mutated cell lines PB1 showed a promising activity. It can be hypothesized that
inhibition of DDR2 by PB1 could abrogate SHP2 and, as a consequence, KRAS pathway
could be less active. Most of the KRAS cell lines are mesenchymal cell lines where DDR2
expression is higher and SHP2 plays a key role. Conclusion: The scarcity of targeted
treatment options for lung SCC makes it a priority to develop new drugs for this disease.
DDR2 is strongly related to SCC, and PB1 has emerged as a new potential drug to
abrogate its activity and as a result to be a possible treatment to this group of patients.
Bibliography: 1) Miao et al. BMC Cancer. 2014 May 24; 14:369. 2) Payne et al. J Thorac
Oncol. 2014 Jun; 9(6):900-4. 3) Walsh et al. Matrix Biol. 2011 May; 30(4): 243-247. 4) Iwai
et al. Biochem. J. (2013) 454, 501-513.
69
Poster 13
Ana Gimenez Capitan
Ana Gimenez-Capitan1, R. Jonas A. Nilsson2,3,4, Niki Karachaliou5, Jordi Berenguer2,
Pepijn Schellen2,4, Cristina Teixido1, Justine L. Kuiper6, Esther Drees2, Magda
Grabowska2, Marte van Keulen7, Danielle A. M. Heideman8, Erik Thunnissen8, Anne-Marie
C. Dingemans9, Santiago Viteri5, Bakhos A. Tannous7, Ana Drozdowskyj10, Rafael Rosell
1,5,11,12, Egbert F. Smit6, Thomas Wurdinger1,3,71Pangaea Biotech SL,; 2VU University
Medical Center; 3 Umea University, Umea, Sweden; 4thromboDx B.V.; 5Translational
Research Unit, Dr Rosell Oncology Institute, Quirón Dexeus University Hospital; VU
University Medical Center, 1,5 Barcelona, Spain 2, 4, 6 Amsterdam, the Netherlands
EML4-ALK rearrangement in blood platelets and outcome to
crizotinib in non-small-cell lung cancer patients
Background: Non-small-cell lung cancer (NSCLC) with EML4-ALK rearrangements is
sensitive to crizotinib. Despite initial response most patients will relapse. Monitoring
EML4-ALK rearrangements during the treatment may help identify them. Challenges
associated with serial tumor biopsying have spurred the search for non-invasive bloodbased assays to allow frequent assessment of biomarkers. Platelets can sequester
RNA released by tumor cells and are an attractive source for non-invasive biomarker
assessment.
Methods: EML4-ALK rearrangements were analyzed by reverse transcription-polymerase
chain reaction (RT-PCR) in platelets and plasma isolated from blood obtained from 77
NSCLC patients, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients
with EML4-ALK-rearranged tumors treated with crizotinib, EML4-ALK rearrangements in
platelets were correlated with progression-free survival (PFS) and overall survival (OS).
Results: The study was designed with three parallel objectives: to determine the sensitivity
and specificity of detecting EML4-ALK rearrangements in platelets with plasma serving as a
control biosource; to examine the potential impact of EML4-ALK rearrangement in platelets
on outcome to crizotinib; to test the feasibility of monitoring patients throughout treatment
with EML4-ALK rearrangement assessment in platelets. RT-PCR demonstrated 65%
sensitivity and 100% specificity for detection of EML4-ALK rearrangements in platelets.
In the subset of 29 patients treated with crizotinib, PFS was 3.7 months for patients
with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (P=0.02).
Monitoring EML4-ALK rearrangements in platelets of one index patients over a period of 30
months revealed crizotinib resistance two months prior to radiographic disease progression.
Conclusions: Our study is the first to examine the EML4-ALK rearrangement in platelets
obtained from patients with NSCLC. Platelets may provide a useful source for the
non-invasive assessment of EML4-ALK rearrangements. Serial analyses of EML4-ALK
rearrangements in platelets may help improve clinical decisions based on radiographic
imaging alone by providing advance signals of therapy resistance.
POSTER ABSTRACTS
Poster 14
Maria Gonzalez Cao
M. Gonzalez-Cao1, (C. Mayo-de-las-Casas2, M.A. Molina-Vila2, L. De Mattos-Arruda3,
E. Muñoz3, J.L. Manzano4, J. Cortes3, J.P. Berros5, M. Sanmamed6, A. Gonzalez6, C.
Alvarez5, S. Viteri1, N. Karachaliou1, S. Martin Algarra6, J. Bertran-Alamillo2, N. Jordana-Ariza2, R. Rosell1,2,7.)
1Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus
University Hospital, Barcelona; 2Pangaea Biotech S.L, Barcelona; 3Vall d?Hebron,
Barcelona, Spain; 4Catalan Institute of Oncology, Hospital Germans Trias i Pujol Badalona,
Barcelona, Spain; 5Hospital Central Asturias, Oviedo, Spain ; 6CUN, Pamplona, Spain;
7MORe Foundation, Barcelona, Spain
BRAF mutation analysis in circulating free tumor DNA of melanoma
patients treated with BRAF inhibitors
Background: BRAFV600E is the most frequent somatic point mutation in metastatic
melanoma, providing a unique molecular marker for this malignancy. Tumors carrying
this mutation are primary candidates for BRAF-targeted therapy. Although metastatic
melanoma patients usually have sufficient tumor tissue available for genetic analyses,
detection of BRAFV600E in blood could have prognostic and predictive value and be
useful for monitoring response to therapy.
Methods: We developed a rapid and sensitive methodology based on a quantitative
5?-nuclease PCR in presence of a peptide-nucleic acid (PNA) for the detection of
BRAFV600E mutation in circulating-free DNA (ctDNA) isolated from plasma and serum.
The assay was validated in 92 lung and colon cancer as well as melanoma archival blood
samples with paired tumor tissue (40 wild type [wt] and 52 BRAFV600E). The correlation
of BRAFV600E ctDNA with clinical parameters was explored in 22 metastatic melanoma
patients treated with BRAF inhibitors.
Results: Our assay can detect and quantify BRAFV600E in mixed samples with as
little as 0.005% mutant DNA (copy number ratio 1:20,000). The assay had a specificity
of 100% and a sensitivity of 57.7%. For the 22 melanoma patients treated with
BRAF inhibitors, median progression-free survival (PFS) was 3.5 months for those
with BRAFV600E in pretreatment ctDNA compared to 13.6 months for those without
(p=0.026).
Conclusions: The sensitive detection and accurate quantification of low abundance
BRAFV600E alleles in serum and plasma using our assay can be useful for predicting
treatment activity.
71
Poster 15
Carles Hernandez-Ferrer
Carles Hernandez-Ferrer (presenting author), Ines Quintela, Katharina Danielski, Angel
Carracedo, Luis Pèrez-Jurado, Juan R Gonzalez
(1) Centre de Recerca en Epidemiologia Ambiental - Parc de Recerca Biomédica de
Barcelona (2) Centro Nacional de Genotipado-ISCIII. Universidade de Santiago de
Compostela (3) Affymetrix (4) Universitat Pompeu Fabra Departament de Cienxies
Experimentals i de la Salut Unitat - de Recerca en Genética (5) Centre de Recerca en
Epidemiologia Ambiental - Parc de Recerca Biomédica de Barcelona
Analyzing SNPs, CNVs, inversions and mosaicisms association
studies using Affymetrix CytoScan technologies
Genome-Wide Association Studies (GWAS) interrogates a large number of genetic
variants (SNPs) with high-throughput technologies. To date, GWAS have led to many
scientific discoveries including cancer or asthma among others. Nonetheless, SNPs have
explained relatively little of the total heritability of complex diseases. In order to overcome
this difficulty, some researchers are being analysing other structural variants (SVs) like
copy number variants (CNVs), mosaicisms or inversions in complex diseases.
In the past five years, commercial business, such Affymetrix and Illumina, produced
dense SNP arrays that made possible to genotype many markers in a single assay.
For the Svs studies, custom arrays and specific-disease arrays have been developed.
An example of them is Affymetrix CytoScan family, that include a high density array
(CytoScan HD) and the light version array (CytoScan 750K). This family of arrays was
designed to proved a broad overview of the whole genome since they include markers
for constitutional and cancer genes and OMIM and RefSeq genes. The most common
software to analyse CytoScan data is called Chromosome Analysis Suite (ChAS). Overall
the benefits, the usage of ad hoc software has some limitations. For that , an R package
called affy2sv has been created. The package includes the advantages and functionality
provided by ChAS by incorporating new functionalities that make possible the analysis of
CytoScan HD data with other existing tools (PLINK, PennCNV, MAD, GADA, ...) as well as
data visualization. Therefore, affy2sv will facilitate the analysis of CytoScan data in SNP,
CNV, mosaicisms or inversion association studies by using, for instance, pipelines under
R environment. New features are illustrated by analysing two cohorts of 624 individuals
from Toronto and Nijmegen for which CytoScan HD array data were obtained.
POSTER ABSTRACTS
Poster 16
Petra Hyrossova
Petra Hyrossova (presenting author), Elisabetta Stanzani, Fina Martínez-Soler, Karen
Roqueta Capilla, Noemi Vidal, Pepita Gimènez-Bonafè, Avelina Tortosa, Jose-Carlos Perales
(1),(2),(3),(4),(6),(7),(8) University of Barcelona, Spain (5) Bellvitge Hospital, Spain
Metabolic profiling of mesenchymal GICs
Recent studies demonstrated that glioblastoma (GBM), the most malignant primary brain
tumor in adults, exhibited remarkable cellular heterogeneity. Only a small subpopulation
accounts for GBMs aggressive and resistant nature, glioblastoma initiating cells (GICs).
Metabolic profile of GBM tumor in bulk tend to show aerobic glycolysis (Warburg
phenotype), whereas alterations in GICs metabolism remain to be elucidated. The aim
of this study is to identify metabolic adaptations of primary GBM mesenchymal GICs
compared with primary culture maintained in differentiated state, more representative of
the bulk of tumor. GBM post-surgery specimens have been maintained in two different
growth conditions: FBS-containing media (differentiated cells growing in monolayer) and
FBS-free media supplemented with bFGF and EGF (non-adherent cells forming spheres,
GICs). Expression of typical mesenchymal stem markers was found in our primary lines
of GICs. These cells present more oxidative metabolism than the monolayer specimens.
High resolutions respirometry identified higher basal oxygen consumption in GICs.
Additionally, glucose metabolism of GICs was less glycolytic (lower glucose consumption
and lactate production). GICs have been shown to survive lethal environmental stress
like nutrient deprivation. In these conditions gluconeogenic pathway could provide
needful metabolites to ensure cell growth and survival. Interestingly we found that GICs
are overexpressing PEPCK-M, a key cataplerotic enzyme connecting mitochondrial and
glycolytic intermediates. Moreover, the expression of PEPCK-M increased when GICs
undergo autophagy. In conclusion, we demonstrate that GICs present mainly oxidative
metabolism whereas the cells of tumor bulk rely on aerobic glycolysis.
Changes in PEPCK-M expression levels in these two cell populations point to the
possible involvement of the stromal carbon sources (i.e., lactate and glutamine) in
supporting tumor growth.
73
Poster 17
Laura Isus
Laura Isús1 (presenting author), Mireia Herrando-Grabulosa2, Caty Casas2 and Patrick
Aloy1,3
(1) Institute for Research in Biomedicine (IRB Barcelona), Joint IRB-BSC Program in
Computational Biology. (2) Group of Neuroplasticity and Regeneration Department of Cell
Biology, Physiology and Immunology Institute of Neurosciences, Universitat Autónoma
de Barcelona, and Centro de Investigación Biomèdica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED) Bellaterra, Spain. (3) Institució Catalana de Recerca I
Estudis Avançats (ICREA)
A Network approach to Spinal Cord Injury
Spinal Cord Injury (SCI) represents a severe health problem associated with lifetime
disabilities. Immediate cell death occurring after SCI is followed by a progressive death
of neurons and degeneration. Depending on the severity and the proximity to the soma
of the axonal injury, spinal motoneurons (MNs) may evolve to a retrograde degeneration
reaction or to a regenerative process [1]. Combining proteomic data with physical and
functional interaction information can provide further insights into the dynamic behavior
and mechanisms involved in the degeneration and regeneration of spinal motoneurons.
We propose a directed integrative approach to decipher the distinct molecular and
cellular changes that contribute to each type of process and particularly in the death
mechanisms and the characteristic neuropatic pain associated with the degenerative
process. Combining proteomic data with protein-protein interaction networks specifically
containing disease-associated genes and their direct interactors, can help us to
razionalize our findings and may provide new candidate and interesting proteins for
further analyses. Comparing GSEA analysis of our lists of candidates and networks with
classical functional enrichment analysis (DAVID) we have been able to identify distinct
enriched pathways (motives) between the degenerative and the regenerative process
instead of general GO terms and KEGG pathways common to both models and many
other disorders. In conclusion, some motives become siginificant only when direct
interactors were included in the GSEA (e.g., Anoikis and Autophagosome fusion events)
showing that by mapping our candidates to an interaction network we are increasing the
statictical power of our analysis.
POSTER ABSTRACTS
Poster 18
Samira Jaeger
Samira Jaeger (presenting author)(1), Rodrigo Arroyo (1), Ana Igea (2), Victor Alcalde (1),
Begoña Canovas (2), Modesto Orozco(1,3), Angel R. Nebreda (2,4) and Patrick Aloy (1,4)
(1) Joint BSC-CRG-IRB program in Computational Biology, Institute for Research in
Biomedicine (IRB Barcelona). c/ Baldiri i Reixac 10-12. 08028 Barcelona, Catalonia, Spain (2)
Oncology program, Institute for Research in Biomedicine (IRB Barcelona). c/ Baldiri i Reixac
10-12. 08028 Barcelona, Catalonia, Spain (3) Department of Biochemistry and Molecular
Biology, University of Barcelona. 08028 Barcelona, Catalonia, Spain (4) Institució Catalana
de Recerca i Estudis Avançats (ICREA). Pg. Lluís C
Pathway crosstalk quantification reveals synergistic drug
combinations against breast cancer
Breast cancer is the second most common cancer type in the world, and the leading
cause of cancer death in women (Hutchinson 2010). Ongoing efforts in cancer drug
discovery yielded a shift towards mechanism-based and target-oriented strategies,
particularly aiming at modulating specific molecular pathways and the tumor
microenvironment (Gibbs 2000, Mills 2012). Yet, despite the therapeutic progress and
an expanding repertoire of new anti-cancer agents, therapy failure due to multiple
compensatory mechanisms remains a major challenge in the treatment of breast
cancer (Sierra et al, 2010; Tsang & Finn, 2012; Vogel et al, 2002). Combinatorial therapy
is among the most promising strategies for improving clinical outcomes in cancer
treatment. Combining drugs allows for impeding compensatory mechanisms, often
conferring to treatment failure, at drug concentrations that are less toxic and harmful
than the high doses of single drugs (Lehar et al, 2009), which are commonly required to
achieve a similar effect. Here, we present a computational framework to infer synergistic
drug combinations for breast cancer therapy. Given the importance of compensatory
mechanisms, such as, functional redundancy and pathway crosstalk, we propose a
network-based method for quantifying crosstalk between pathways to uncover drug
combinations, which are able to prevent crosstalk between pathways implied in breast
cancer. We apply this measure to a set of approved and experimental breast cancer
drugs to identify combinations, which efficiently diminish pathway crosstalk and thereby
increase clinical efficacy. Subsequently, we experimentally validate a significant sampling
of the most promising drug combinations in several breast cancer cell lines and confirm
the synergistic effect between two drugs in a MCF-7 xenograft, proving the synergy of
this combination in vivo as well as emphasizing the clinical relevance of our strategy.
75
Poster 19
Eloisa Jantus Lewintre
Sandra Gallach1, Silvia Calabuig1,3, Ana Blasco3, Ricardo Guijarro3, Miguel Martorell3,
Carlos Camps1, 3, 5 , Eloisa Jantus-Lewintre1,2
1Molecular Oncology Laboratory, General University Hospital Research Foundation,
Valencia/SPAIN 2 Department of Biotechnology, Polytechnic University of Valencia, Valencia/
SPAIN, 3 Department of Medicine, University of Valencia, Valencia/SPAIN, 4 Prince Felipe
Research Centre, Valencia/SPAIN 5 General University Hospital, Valencia/SPAIN
MicroRNA expression in tumor tissue is related to survival in earlystage NSCLC patients
Background: MicroRNAs (miRNA) are a class of small RNAs that regulate gene
expression, and are implicated in several diseases including cancer. The aim of this study
was to analyze the prognostic implications of deregulated miRNAs identified by NGS in a
previous study performed on resected-NSCLC tumor samples.
Methods: Fresh-frozen tumor and normal adjacent lung tissue samples (N=195) were
obtained by surgical resection from NSCLC patients and storage in RNAlater® at -80
ᵒC until analysis. RNA was isolated biological specimens by Trizol based-methods. 22
deregulated miRNA were analyzed in paired tumor/normal samples by RTqPCR using
TaqMan® microRNA assays. Statistical analyses were considered significant at p<0.05.
Results: Patient’s median age was 64 years [26-85], 88.2% were male, 66.7% had
good performance status (PS=0), 39.5% were adenocarcinomas and 54.9% presented
stage I at the time of the diagnosis. For survival analysis, continuous variables were
dichotomized, using the median expression of each miRNA as a cutoff. Of the 22 miRNAs
analyzed only miR-21 and miR-188-5p had prognostic value. We found that patients
with high levels of miR-21 and miR-188-5p had a significant reduction in PFS and OS
rates. Interestingly, the group of patients with the combined high expression of both
miRNAs (miR-21high & miR-188-5phigh) showed shorter PFS and OS (Table 1). Clinicopathological and analytical variables were included in the multivariate analysis revealing
that combined miRNAs is an independent prognostic marker for PFS (HR 0.485 [0.3130.753]; p= 0.001) and OS (HR 0.389 [0.237-0.638]; p<0.0001].
Conclusions: MiR-21 and miR-188-5p seem to have a prognostic role in NSCLC, and the
combination of both could be an independent prognostic marker in early-stage NSCLC.
POSTER ABSTRACTS
Poster 20
Eloisa Jantus-Lewintre
E. Jantus-Lewintre (1) (presenting author), M. Usó (2), R. Sirera (3), S. Calabuig (1), A. Blasco
(4), R. Guijarro (5), J. Forteza (6), C. Camps (1,2,4)
(1)Molecular Oncology, Fundación Investigación Hospital General Universitario de Valencia,
Spain (2) Department of Medicine, Universitat de Valéncia, Spain (3) Department of
Biotechnology, Universitat Politécnica de Valéncia, Spain (4) Medical Oncology, Hospital
General Universitario Valencia, Spain (5) Thoracic Surgery, Hospital General Universitario
Valencia, Spain (6) Instituto Valenciano de Patología, Spain
Immune checkpoint score is an independent prognostic biomarkes
and correlates with intratumoral CD8+ cells infiltration in resected
NSCLC
Background: Immune checkpoints blockade, which activate antitumor immunity, has
demonstrated promising clinical results in NSCLC. In this study, we have investigated
the prognostic role of immune-checkpoint expression markers and its correlation with
immune-cells infiltration as well as their prognostic value in resected NSCLC.
Material and methods: RNA was isolated from fresh-frozen lung specimens (tumor
and normal) (n=178). RTqPCR was performed to analyze the expression of CTLA4, PD1
and PDL1, and gene expression was normalized against CDKN1B, GUS and ACTB
as endogenous control. These data were used to develop a gene expression score.
The presence of CD8+cells was assessed in tumor and stroma compartments in 84
FFPE samples by immunohistochemistry (IHC). All statistical analyses were considered
significant at p< 0.05.
Results: A multivariate model including CTLA4 and PD1 was created and absolute
regression coefficients were used to calculate the immune-checkpoint score (ICS): (PD1
x 0.116) + (CTLA4 x 0.0589). We found a significant association between high ICS and
CD8+ infiltrating cells in the tumor compartment (p=0.012). Kaplan-Meier survival analysis
showed that patients with high ICS have longer overall survival (OS) [NR vs 40.4 months,
p=0.008] and longer progression free survival (PFS) [82.6 vs 23 months, p=0.009].
Moreover, the presence of CD8+cells in the tumor compartment was significantly
associated with better OS [73.9 vs 40.4 months, p=0.021] and PFS [56.8 vs 23 months,
p=0.026]. Multivariate analysis indicated that ICS and CD8+ cells infiltration were
independent biomarkers of prognosis.
Conclusions: The immune checkpoint score was correlated with the presence of CD8+
cells in the tumor compartment, and both biomarkers provided relevant prognostic
information for a better characterization of early-stage NSCLC. Supported by grants
PI12-02838 and RD12/0036/0025 from ISCIII.
77
Poster 21
Antonio Jauset
Toni Jauset (1) (presenting author), Marie-Eve Beaulieu (1), Daniel Massó-Vallés (1), Jonathan
Whitfield (1), Francesco Paolo Fiorentino (2), Mireia Pesarrodona (3), Erika Serrano (1),
Takashi Kohno (4), Antonio Villaverde (3), Esther Vázquez (3), Jun Yokota (2) and Laura
Soucek (1,5) (1) Vall d’Hebron Institute of Oncology (VHIO), Hospital Vall d’Hebron, Barcelona, Spain (2)
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain (3)
Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Spain (4)
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. (5)
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
Myc inhibition is an effective strategy against different subtypes of
NSCLCb
Personalized cancer therapies are based on the observation that each cancer is defined
by a unique mutational profile. Accordingly, patients are treated using drugs targeting
their own specific oncogenic lesions. However, such drivers are often degenerate
and redundant, so that tumors rapidly evolve around these therapeutic interventions
and develop resistance. An alternative approach is instead to inhibit central and nonredundant nodes in tumorigenesis. Here, we propose targeting Myc, an oncogene
deregulated in the majority of human cancers, as an effective therapeutic strategy against
all subtypes of Non-Small-Cell Lung Cancer (NSCLC), which presents one of the highest
inter-tumor heterogeneities. To pre-clinically validate our approach, we infected a panel of
NSCLC cell lines harbouring a wide variety of mutational alterations with a doxycyclineinducible vector that expresses a Myc dominant negative called Omomyc. Consistent
with previous data based on transgenic expression of Omomyc in various mouse models
of cancer, all cell lines displayed similar sensitivity to Myc inhibition in vitro, regardless of
their mutations, and responded with a significant decrease in proliferation, partial arrest
in G1 and an increase in cell size. Upon expression of Omomyc, we also observed a
consistent increase in MAX protein levels, another member of the Myc network, across
the different cell lines and a higher affinity of MAX for DNA during mitosis, hinting at
additional potential mechanisms of action of Omomyc. To test the effect of Myc inhibition
in vivo, we will transplant orthotopically in immune compromised mice NSCLC cells
that are KRas mutated (A549), EGFR mutated (H1975) or wild-type for both (H1299) and
determine the response to Omomyc expression. Finally, we are currently investigating the
innovative strategy of combining Omomyc-based peptides and nanoparticle technology
to achieve pharmacological Myc inhibition in vivo, thus providing a novel therapeutic
option that would be of utmost interest in the clinic.
POSTER ABSTRACTS
Poster 22
Teresa Juan-Blanco
(presenting author)Teresa Juan-Blanco (1), Miquel Duran-Frigola (1), Patrick Aloy (1,2)
1. Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in
Biomedicine (IRB Barcelona), c/ Baldiri Reixac 10-12, 08028 Barcelona, Spain. 2. Institució
Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluis Companys 23, 08010 Barcelona,
Spain.
IntSide: a web server for the chemical and biological examination of
drug side effects
Drug side effects (SEs) are one of the main health threats worldwide, and an important
obstacle in drug development. Understanding how adverse reactions occur requires
knowledge on drug mechanisms at the molecular level. Despite recent advances, the
need for tools and methods that facilitate side effect identification still remains. Very
recently, we presented a top-down approach to identify chemical and biological drug
features that may be involved in the development of adverse drug reactions (DuranFrigola & Aloy, 2013). We delimited the chemical and biological space for each compound
by gathering molecular properties from major biomedical resources and carried out
an enrichment analysis, associating more than 1,000 SEs with molecular features.†On
the biological side, we considered drug targets and off-targets, pathways, molecular
functions and biological processes. From a chemical viewpoint, we included molecular
fingerprints, scaffolds and chemical entities.† Here, we introduce a web server, named
IntSide, which automates this analysis and enables the quick and easy access to our
findings. Moreover, we further extend the method by integrating additional biological
information, like protein interactions and disease-related genes, to facilitate mechanistic
interpretations. IntSide is available at http://intside.irbbarcelona.org/.† Reference:† JuanBlanco T, Duran-Frigola M, Aloy P. IntSide: a web server for the chemical and biological
examination of drug side effects. Bioinformatics. 2015;31(4):612-613. Duran-Frigola M,
Aloy P. Analysis of chemical and biological features yields mechanistic insights into drug
side effects. Chemistry & biology. 2013;20(4):594-603.
79
Poster 23
Niki Karachaliou
Niki Karachaliou-1 (Presenting author), Ana Drozdowskyj-2, Ana Gimenez-Capitan-3, Carles
Codony-3, Imane Chaib-4, Jose Luis Ramirez-4, Bartomeu Massuti-5, Teresa Moran-4,
Margarita Majem-6, Enriqueta Felip-7, Enric Carcereny-4, Rosario Garcia-Campelo-4,
Santiago Viteri-1, Daniela Morales-Espinosa-1, Rafael Rosell-4
1-Translational Research Unit, Dr Rosell Oncology Institute, Quirón Dexeus University
Hospital, Barcelona, Spain; 2-Pivotal, Madrid, Spain;3-Pangaea Biotech SL, Barcelona,
Spain; 4-Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain; 5Alicante University Hospital, Alicante, Spain; 6 -Hospital Sant Pau, Barcelona, Spain; 7-Vall
d’Hebron University Hospital, Barcelona, Spain;
BIM and mTOR expression levels predict clinical outcome to erlotinib
in EGFR-mutant non-small-cell lung cancer (NSCLC) patients
Background: Response to erlotinib occurs in 60% of in EGFR-mutant NSCLC patients,
but overall survival (OS) is not different from patients receiving upfront chemotherapy.
Priming the pro-apoptotic protein BIM, induced sensitivity to erlotinib in EGFR-mutant
cell lines. BIM was related to response and progression-free survival (PFS) in clinical
tumor samples. The mammalian target of rapamycin (mTOR) negatively regulates
apoptosis and could influence response to erlotinib.
Methods: We assessed the levels of BIM, and mTOR mRNA expression and correlated
our findings with response and OS in 57 EGFR-mutant NSCLC patients treated with
erlotinib or chemotherapy in the EURTAC trial.
Results: Median age 65; 70.2% female; 59.6% never-smokers; 91.2% adenocarcinoma.
Response rate was 88.9% for erlotinib-treated patients with high total BIM levels,
compared to 22.2% for p with low/intermediate total BIM levels (P=0.0027). The
sensitivity/specificity of total BIM as a predictor of response to erlotinib was highly
significant (AUC=0.80; P=0.0056). OS was 35.8 months (m) for patients with high and
17.7 m for patients with low/intermediate total BIM (P=0.023). Among patients with high
total BIM, OS was 35.8 m for patients with low/intermediate mTOR levels, compared to
20.3 m for patients with high mTOR levels (P=0.4848). In contrast, mTOR did not affect
OS in patients with low/intermediate BIM (17.5 m vs 25.1 m; P=0.9498).
Conclusions: Our findings highlight the potential usefulness of BIM mRNA as a predictive
biomarker of response in EGFR-mutant NSCLC patients. Those with low BIM expression
could derive only a meager benefit from treatment with EGFR TKIs alone but could
benefit from synthetic lethality combinations. Those with high BIM expression could
benefit from erlotinib or akin EGFR TKIs, but the analysis of mTOR could further improve
outcome by selecting patients with high mTOR for combination therapy with EGFR TKIs
and mTOR inhibitors.
POSTER ABSTRACTS
Poster 24
Ege Riza Karagur
Ege Riza Karagur (1), Ramazan Mammadov (2), Hakan AKCA (1)
(1) Pamukkale Universiyt, School of Medicine, Department of Medical Biology Denizli,
Turkey. (2) Pamukkale Universiyt, Faculty of Arts & Sciences, Department of Biology?,
Denizli, Turkey.
Cyclamen graecum and Cyclamen pseudibericum Plant Extracts
Induces miR-145, miR-146 and miR-200c Expression is Strongly
Inhibited Invasion and Migration Capacit
In this study, Activities of ethanol solvent extracts obtained from tubers and leaves of
Cyclamen graecum Link and C. pseudibericum Hildebr (Primulaceae) were investigated
antiproliferative activities on PC9, PC14 and A549 non-small cell lung cancer
cells. Proliferation and viability were analysed by the luminometric method using a
CytotoxGloÆ kit (Promega, Madison, WI, USA). Values for the concentration at which
50% inhibition occurred (IC50) were calculated for two plant extracts. The test was
carried out the concentration dependent assay from 1?g/ml to 1000 ?g/ml. We found that
two plant extracts have cytotoxic effects on PC9, PC14 and A549 NSCLC cells but that
C. graecum has the strongest cytotoxic effect even in the lowest extract concentration
tested (30,31 ng/µL). The extracts inhibited the invasion ability of PC9, PC14 and A549
cell lines. In addition, we performed real-time PCR assays to determine the expression
of invasion and migration related several miRNAs on PC9, PC14 and A549 cell lines. We
observed that expression levels of miR-200c significantly increased on PC14 and A549
cell lines, treated with C. pseudibericum extract. Also, expression levels of miR-146
significantly increased in PC14 and A549 cell lines when C. graecum extract treated. We
evaluated that the extracts can suppress NSCLC invasion by induction of miR-145, miR146 and miR-200c microRNA expression.
81
Poster 25
Hakan Kucuksayan
Hakan Kucuksayan(1) and Hakan Akca(1)
(1)Medical Biology Department, School of Medicine, Pamukkale University, Kinikli, Denizli,
Turkey
Downregulation of SATB2 is critical for induction of EMT, invasion
and stemness in NSCLC cells
Lung cancer is one of the most common causes of death by cancer worldwide with
less than 10-15% of survival rate at 5 years. Epithelial-mesenchymal transition (EMT)
is a key event in invasion of cancer. There are lots of regulator proteins responsible for
inducation of EMT, but underlying mechanisms are still unknown. SATB2 is a nuclear
matrix-associated transcription factor and epigenetic regulator that is involved in
osteoblastic differentiation and craniofacial patterning. Although repression of SATB2
expression by several miRNAs is associated with EMT in colorectal cancer cells, the
molecular mechanisms of SATB2-related suppression of EMT is poorly understood.
Also, it is still unknown whether SATB2 is regulated by various EMT indicators. TGF-ß, a
strong indicator of EMT play an key role in the EMT and invasion of lung cancer. In our
results firstly indicated that siRNA-mediated knockdown of SATB2 leads to morphological
changes such as an elongated-shape and fibroblast-like morphology, induction of
EMT and invasion by induction of Twist and Zeb1 expression in NSCLC cells. TGF-ßtreatment significantly suppress SATB2 expression in A549 cells, but not in H1650 cells.
Furthermore, down-regulation of SATB2 promotes TGF-ß- induced EMT and invasion
in A549 and H1650 cells. Our findings indicated that suppression of SATB2 expression
might be a critical role for TGF-ß- induced EMT and invasion in A549 and H1650 cells.
We observed that Twist over-expression in NSCLC cells leads to significantly inhibition
of SATB2 expression. In addition, we firstly showed that knockdown of SATB2 result in
enhanced expression of stemness markers such as CD44 and Sox-2 in NSCLC cells.
Collectively, our experiments indicated that SATB2 could be a key regulator on EMT,
invasion and stemness properties of NSCLC cells.
This study is supported by TUBİTAK grant number 114S007
POSTER ABSTRACTS
Poster 26
Arànzazu Lafuente Sanchis
Lafuente-Sanchis Arànzazu (presenting author)1, Zúñiga Angel2, Galbis-Caravajal Josè
Marcelo3, Cremades Antonio4
1,2 Molecular Biology Department, Hospital Universitario de la Ribera (Alzira, Valencia) Spain
3 Thoracic Surgery Department, Hospital Universitario de la Ribera (Alzira, Valencia) Spain 4
Anatomic Pathology Department, Hospital Universitario de la Ribera (Alzira, Valencia) Spain
Analysis of ERCC1, BRCA1 and RRM1 expression in non-small cell
lung cancer and its relationship with clinicopathologic characteristics
The identification of molecular markers with prognosis value and its relationship with
patients’ clinicopathologic characteristics is of great importance for cancer diagnosis,
and ultimately for designing targeted therapies, role that has been recently associated to
ERCC1, BRCA1 and RRM1 in lung cancer (LC). However, most of the studies performed
in LC are focus on advanced non-small cell lung cancer (NSCLC) patients. Differences
in the expression of these genes in the first stages of the disease could open a new
strategy to detect patients with risk of relapse who could benefit from individualized
chemotherapeutic regimens. The aim of this study was to analyze by qRT-PCR the
expression of ERCC1, BRCA1 and RRM1 in primary tumoral lung tissues from 55
NSCLC patients and correlate it with clinicopathologic characteristics. The analysis was
performed using the Kruskal-Wallis analysis followed by the Mann-Whitney t-test. The
minimum level of significance was established at p<0.05.
Our study didn’t find any significant difference in BRCA1 expression between the different
NSCLC stages analyzed, although patients staged at phase IB showed lower ERCC1
expression than those staged at IA (p<0.05) and IIA (p<0.05). Regarding RRM1, we found
that staged IA patients had a gene expression significantly higher than patients staged at
more advanced phases (IB: p<0.05; IIA: p<0.01; IIB: p<0.05). Any difference was found in
BRCA1 and RRM1 expression regarding age, gender, histological type or smoking status,
while ERCC1 expression was exclusively found higher in the older patients (p<0.01).
These results show that the expression level of ERCC1 and RRM1 is correlated with
pathological staging and age in NSCLC patients, finding that could be useful in order to
improve the diagnosis and the targeted treatments in these groups of patients.
83
Poster 27
Ettore Luzi
Ettore Luzi1, Francesca Marini1, Simone Ciuffi1, Gianna Galli and Maria Luisa Brandi1
1Laboratory of Neuroendocrine Complex Diseases, Center on Endocrine Hereditary Tumors,
AOUC, Department of Surgery and Translational Medicine , University of Firenze (ITALY)
[email protected]
The Gene Regulatory Network (GRN) Menin-miR-24 is involved in the
cancer cells biology by controlling the pri-miR-24 processing.
MEN1 gene, a tumour suppressor gene, encodes the menin protein. Loss of
heterozygosity (LOH) at 11q13 is typical of MEN1 tumors in agreement with the
Knudson’s two-hit hypothesis. We previously showed that the MEN1 parathyroid
tumorigenesis is under the control of a “incoherent feedback loop” between miR-24-1
and menin protein that generates a “Gene Regulatory Network” (GRN) that mimics the
second hit of Knudson’s hypothesis and that could buffer the effect of the stochastic
factors that contribute to the onset and progression of this diseases. Here we show, in
BON1 cell line derived from a lymphnode metastasis of a human carcinoid tumour of the
pancreas, that menin binds specifically to the primary RNA sequence pri-miR-24-1 by
inducing miR processing. This result shows a novel mechanism whereby menin, as RNAbinding protein, facilitates the processing of its specific miR by regulating the dynamics
of menin-miR-24 Gene Regulatory Network at level of pri-miRNA processing.
This Gene Regulatory Network open the possibility to design a synthetic circuit to
modulate the Menin tumor suppressor activity.
POSTER ABSTRACTS
Poster 28
Daniela Morales-Espinosa
D. Morales-Espinosa (Presenting author)1, N. Karachaliou1, A. Drozdowskyj2, A. GimenezCapitan1, , T. Moran3, E. Carcereny Costa3, M. Cobo4, M. Domine2, I. Bover5, C. Camps6,
M. Provencio Pulla2, A. Vergnenegre7, G. Lopez-Vivanco8, M. Majem Tarruella1, S. Viteri1, B.
Massuti Sureda9, R.Rosell3 .
1-Instituto Oncológico Dr Rosell, Hospital Universitario Quirón Dexeus, Barcelona, Spain,
2-Pivotal, Madrid, Spain 3-Institut Catala d’Oncologia, Hospital Germans Trias i Pujol,
Badalona, Barcelona, Spain, 4- Hospital Regional Universitario Carlos Haya Malaga, Spain
5-Mallorca, Spain 6-Valencia, Spain 7-CHU, Limoges Cedex,FRance, 8-Hospital Quirón
Vizcaya, Spain 9-Spanish Lung Cancer Group (GECP/SLCG); Alicante University Hospital,
Alicante, Spain
PALB2 mRNA Expression as a Predictive and Prognostic Marker
in Advanced Non-Small-Cell Lung Cancer Patients Treated with
Cisplatin-Docetaxel Chemotherapy
Background: The Spanish Lung Cancer Group (SLCG) undertook an industry-independent,
two biomarker-directed, randomized trial in advanced NSCLC. The study (NCT00617656/
GECP-BREC) compared non-selected cisplatin-based chemotherapy with therapy
customized according to BRCA1/RAP80 mRNA levels. The trial was closed prematurely
due to a detrimental effect in the biomarker-directed arm. Further genetic analysis defined
PALB2, the bridging molecule that connects BRCA1 and BRCA2, as a promising biomarker
to elucidate DNA repair mechanisms.
Methods: We assessed mRNA levels of PALB2, RIF1, 53BP1, RNF8 in tissue from 177
cisplatin plus docetaxel-treated NSCLC patients in the BREC trial. PFS, OS and response
were assessed.
Results: Median age 62; 79.1% male; 51.4% adenocarcinoma. PFS was 5.6 months (m)
for patients with high/intermediate (H-I) PALB2 and 4.1 m for patients with low (L) PALB2
(p=0.0018). OS was 13.2 m for patients with H-I PALB2 compared to 9.9 for patients with
L PALB2 (p=0.0377). In the univariate analysis, H-I PALB2 was a marker of longer PFS (HR
= 0.56, 95% CI, 0.38, 0.80; p=0.002) and OS (HR = 0.64, 95% CI, 0.41, 0.98; p=0.0394). In
the multivariate analysis, only H-I PALB2 was associated with longer PFS (here HR=0.56
and p=0.0022) and OS (HR=0.61 and p=0.0343). 49.5% of patients with H-I PALB2 were
responders, compared to only 28% with L PALB2 (p=0.0131). No significant differences were
found for PFS, OS or response according to expression status of the other 4 biomarkers.
Conclusions: PALB2 is a predictive and prognostic biomarker in advanced NSCLC patients
treated with docetaxel plus cisplatin. The BRCA1-PALB2-BRCA2 network is a critical
determinant of responsiveness to DNA interstrand cross-linking agents and antimicrotubule
agents. In our study, BRCA1 had no effect on treatment outcome of this population. PALB2
was found to be a strong marker to predict sensitivity to antimicrotubule agents, without
affecting sensitivity to DNA damage-based chemotherapy.
85
Poster 29
Raimon Puig de la Bellacasa
Raimon Puig de la Bellacasa (presenting author) (1), GaÎl Rouè (2), Patricia Balsas (2),
Patricia Pèrez-Galàn (2), Jordi Teixidó (1), Dolors Colomer (2), Josè I. Borrell (1)
(1) Grup d’Enginyeria Molecular (GEM), Institut Químic de Sarri a (IQS), Universitat Ramon
Llull (URL) (2) Institut d’Investigacions M ediques August Pi i Sunyer (IDIBAPS)
New family of pyrido[2,3-d]pyrimidines as a BCR kinase inhibitors for
B lymphoid malignancies
A new family of 4-aminopyrido[2,3-d]pyrimidines active against non-Hodgkin’s
lymphomas (NHLs) is obtained. Among these compounds, PB2 inhibits the most
upstream tyrosine kinases in the B cell receptor (BCR) signaling pathway which are
involved in the mature B cell neoplasms. Thus, PB2 showed antiproliferative activity at 24
h and 48 h against a panel of 20 NHLs cell lines with GI50 ranging from 1.3 to 6.9 microM
at 24 h, and 1.4-7.2 microM at 48 h, being this effect related to a significant (20-90%)
inhibition of the phosphorylation of the BCR-related kinases Btk, Syk, and Lyn. Most
importantly, PB2 was able to induce a 63% reduction in Rec-1 cell proliferation, which
was significantly greater than the 31% and 3% blockade of proliferation observed after
cell treatment with R406, a Syk inhibitor, and ibrutinib, a Btk inhibitor, respectively. The
computational blind docking and ligand binding within the pockets of Btk, Syk and Lyn
kinases showed that compound PB2 presents the same kind of interactions of described
cocrystallized inhibitors.
POSTER ABSTRACTS
Poster 30
Pere Roca-Cusachs
Alberto Elosegui-Artola (1), Roger Oria (1,2), Anita Kosmalska (1,2), Xavier Trepat (1,2,3), Pere
Roca-Cusachs (1,2) (presenting author).
(1) Institute for Bioengineering of Catalonia (IBEC) (2) University of Barcelona (3) Institució
Catalana de Recerca i Estudis Avançats (ICREA)
Matrix mechanosensing and oncogene activation by talin and
integrin bond dynamics
Alterations in tissue rigidity and composition are not only a hallmark but also a driving
force of tumorigenesis. However, the molecular mechanisms by which cells detect
extracellular matrix (ECM) rigidity and density, and then signal to the nucleus to drive
gene expression and malignancy, remain unknown. Here we show that sensing of ECM
stiffness and density is determined by force-induced activation of talin, which leads to
localization of the YAP oncogene to the nucleus. By combining theoretical modelling with
biochemical and biophysical force measurements on cells, we demonstrate that force
transmission from the actomyosin cytoskeleton to the ECM is driven by the dynamic
collective action of integrin-fibronectin clutches. Those clutches experience a rate of
force loading determined by ECM rigidity, setting a threshold above which force can
activate talin before the clutch unbinds. For ECM rigidities above this threshold, talin
activation leads to adhesion growth and reinforcement, increased force transmission,
and YAP localization to the nucleus. We further show that the threshold rigidity governing
mechanosensing and YAP activation can be tuned according to a quantitative clutch
model by modifying parameters such as fibronectin receptor density or integrin ligation.
Our findings clarify the key factors governing the detection and transduction of matrix
rigidity and density by cells, providing a quantitative mechanistic link between tissue and
molecular mechanical properties and the major YAP signaling pathway.
87
Poster 31
Carolina Ruivo Pereira
Carolina Pereira (1) (presenting author), Pol Gimenez-Xavier (1), Gonzalo Gómez (2), Enric
Condom (3), Alberto Villanueva (4), David Pisano (2), Montse Sanchez Cespedes (1)
(1) Genes and Cancer group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical
Research Center. Hospitalet de Llobregat, Spain. (2) Bioinformatics Unit, Structural Biology
and BioComputing Programme, Spanish National Cancer Centre. Madrid, Spain. (3)
Pathology Department, Bellvitge University Hospital. Hospitalet de Llobregat, Spain. (4)
Translational Research Laboratory, Catalan Institute of Oncology. Hospitalet de Llobregat,
Spain.
Generation of tumorgraft models to characterize novel tumor
suppressor genes implicated in lung carcinogenesis
The extremely poor prognosis and lack of efficient treatments throw lung cancer (LC) to
the top of the deadliest types of cancer worldwide. Throughout the years, the role played
by host genetic variation has been constantly highlighted as the key in determining
tumor onset and progression. In this regard, the discovery of LC-related genes paved
the way to the development of targeted therapies that nowadays are benefiting patients
harboring specific mutational patterns, such as EGFR mutations or ALK rearrangements.
Here, aiming to characterize novel tumor suppressor genes in LC, 8 patient-derived
tumors were subcutaneously or orthotopically engrafted in nude mice for growing and
subsequently carry out exome and transcriptome sequencing. The strategy avoided the
common admixture exhibited by the presence of normal cells in the sample, which were
successfully swept away in the engrafting step, as determined by microsatellite analyses.
Among the 4430 mutations detected by exome-seq, we focused on the 79 ones that
would presumably lead to biallelic gene inactivation, a common feature exhibited by
tumor suppressors: homozygous frameshift indels, nonsense and splicing site mutations.
We then chose to characterize one particular candidate gene, which codifies for a
globular protein that might be involved in the ability of tumors to escape the action of the
immune system. The genetic screening performed resulted in a mutation rate of 5.1%
in 79 tested LC cell lines and of 3.9% in a panel of 179 lung primary tumors.
The complete coding region was cloned in constitutive and inducible systems in order
to restore the expression of the protein in gene-depleted LC-cell lines, and preliminary
results pinpoint that it may indeed trigger an anti-tumoral effect. This in vitro approach is
currently ongoing and hopefully, will enlighten us about its tumor suppressive potential in
the near future.
POSTER ABSTRACTS
Poster 32
Endre Sebestyèn
Endre Sebestyèn (1) (presenting author) Babita Singh (1) Belèn Miñana (1,2) Amadís Pagés
(1) Juan Luis Trincado (1) Juan Valcàrcel (1,2,3) Eduardo Eyras (1,3)
(1) Universitat Pompeu Fabra, Dr. Aiguader 88, E08003 Barcelona, Spain (2) Centre for
Genomic Regulation, Dr. Aiguader 88, E08003 Barcelona, Spain (3) Catalan Institution for
Research and Advanced Studies, Passeig Lluís Companys 23, E08010 Barcelona, Spain
Dissecting cancer-specific splicing regulatory networks
Changes in the regulation of alternative splicing contribute to cancer progression and
several alternative splicing regulatory factors are known to have oncogenic or tumor
suppressor activity. However, a detailed description of the deregulation of splicing factors
and alternative splicing events has not yet been performed on a large scale in cancer.
We have studied the alterations of splicing factors and alternative splicing events in
11 cancer types using data from the Cancer Genome Atlas. We found splicing factor
patterns that are common to multiple cancers, including the depletion of MBNL1 and
QKI genes. We also found cancer specific changes, including the frequent amplifications
of TRA2B, FXR1 and IGF2BP2 in lung squamous carcinomas, RBM39 and SRSF6 in
colon tumors, ESRP1 in breast tumors and the deletion of RBFOX1 in colon tumors
and of RBMS3 in lung squamous carcinomas. The splicing of candidate tumor drivers
is frequently altered in tumors and can separate samples by cancer type. Using motif
enrichment and correlation network analysis, we obtained a description of possible
cancer-specific regulatory programs. Several of these programs include members of the
MBNL family of genes, and we show that MBNL1 regulates the splicing of the candidate
driver NUMA1. We further show this event contributes to cell proliferation. In summary,
we show that alternative splicing changes in tumors contribute to cancer progression
in multiple ways and these changes are controlled by a complex network of splicing
regulators.
89
Poster 33
Maria Vila Casadesús
Maria Vila-Casadesús (1,2) (presenting author), Jan Graffelman (3), Meritxell Gironella (2),
Juan Josè Lozano (1,2)
(1) Bioinformatics Platform, CIBERehd (Barcelona, Catalonia, Spain). (2) Gastrointestinal &
Pancreatic Oncology Team / CIBERehd / IDIBAPS/ Hospital Clínic de Barcelona (Barcelona,
Catalonia, Spain). (3) Department of Statistics and Operations Research, UPC (Barcelona,
Catalonia, Spain).
MiRComb: an R package for analyzing miRNA-mRNA interactions
MicroRNAs (miRNAs) are small RNAs that regulate the expression of target mRNAs by
specific binding on the mRNA 3’UTR and promoting mRNA degradation in the majority
of cases. It is often of interest to know the specific targets of a miRNA in order to study
them in a particular disease context. In that sense, some databases have been designed
to predict potential miRNA-mRNA interactions based on hibridization sequences.
However, one of the main limitations is that these databases have too many false
positives and do not take into account disease-specific interactions. We have developed
an R package (miRComb -http://bioinfo.ciberehd.org/mircomb/-) able to combine miRNA
and mRNA expression data with hibridization information, in order to find potential
miRNA-mRNA targets that are more reliable to occur in a specific physiological or disease
context. This poster summarizes the pipeline and the main outputs of this package
by using a prostate cancer dataset (GSE21032). Globally, we show that the miRComb
package is a useful tool to deal with miRNA and mRNA expression data and helps to
filter the high amount of miRNA-mRNA interactions obtained from the pre-existing miRNA
target prediction databases.
POSTER ABSTRACTS
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CONTACTS
Maria del Rosario Abellàn
Hospital Clínico Valencia
[email protected]
Antonio Ballesta
Analiza
[email protected]
Josep Biayna Rodríguez
IMPPC
[email protected]
Hakan Akca
Pamukkale University
[email protected]
Allan Balmain
USCSF, United States
[email protected]
Sakir Akgun
Pamukkale University
[email protected]
Jordi Banus
IMPPC
[email protected]
Ignacio Blanco
ICO Germans Trias Hospital
iblanco.germanstrias@gencat.
cat
Francisco Almazan Castro
Hospital Germans Trias i Pujol
falmazan.germanstrias@
gencat.cat
Mariano Barbacid
CNIO
[email protected]
Sandra Bonache Real
VHIO
[email protected]
Laura Bonanno
Istituto Oncologico Veneto
[email protected]
Sergio Alonso
IMPPC
[email protected]
Jorge Bardina Santos
IIB Sant Pau. Hospital de Sant
Pau
[email protected]
Rocio Amoretti Villa
IMPPC
[email protected]
Agusti Barnadas
Hospital Sant Pau, Barcelona
[email protected]
Anna Brunet Vega
Fundació Parc Tauli
[email protected]
Oriol Arpí Llucià
IMIM
[email protected]
Marie-Eve Beaulieu
VHIO
[email protected]
Xerxes Arsiwalla
Pompeu Fabra University
[email protected]
Gema Benito
Astra Zeneca
gema.benito@astrazeneca.
com
Diana Buitrago
IRB Barcelona
diana.buitrago@irbbarcelona.
org
Pervin Elvan Arslan
IMPPC
[email protected]
Francisco Aya
Hospital Clinic Barcelona
[email protected]
Daniel Azuara
ICO
[email protected]
Arezki Azzi
Al Imam University
[email protected]
CONTACTS
Ester Bonastre Llort
IDIBELL
[email protected]
Raquel Buj
IMPPC
[email protected]
Fernando Benito
UPF
[email protected]
Marcus Buschbeck
IMPPC / IJC
[email protected]
Elena Beristain
Hospital Universitario Araba-Txagorritxu
elena.beristainmendizabal@
osakidetza.net
Silvia Calabuig
Hospital General de Vaelncia
[email protected]
Cristina Bernado
VHIO
[email protected]
Begoña Cànovas
IRB Barcelona
[email protected]
Elisabet Canto Naves
IIB Sant Pau. Hospital de Sant
Pau
[email protected]
Eva Capdevila-Busquets
IRB Barcelona
eva.capdevila@irbbarcelona.
org
Jose Carbonell-Caballero
CIPF
[email protected]
Cristina Carrato
Hospital Germans Trias i Pujol
[email protected]
David Cordero Romera
ICO
[email protected]
Lídia Feliubadaló
ICO
[email protected]
Carlo Croce
University of Ohio
[email protected]
Aranzazu Fernandez Martinez
Hospital Clinic Barcelona
[email protected]
Cankut Cubuk
Centro de Investigación Príncipe Felipe (CIPF)
[email protected]
Francesco Paolo Fiorentino
IMPPC
[email protected]
Estela Damaso Riquelme
ICO-IDIBELL
[email protected]
Sónia Forcales
IMPPC
[email protected]
Sandra Gallach Garcia
Hospital General de Valencia
[email protected]
Anna Carreras Nolla
IMPPC
[email protected]
Stephanie Davis
Rosell Institute
stephanie.oncorosell@gmail.
com
Meritxell Carrió Llach
IMPPC
[email protected]
Rafael de Cid
IMPPC
[email protected]
Cristina Galvan Casas
Hospital Universitario de
Mostoles
galvancasascristina@gmail.
com
Elisabeth Castellanos
IMPPC
[email protected]
Oscar de la Calle-Martin
Hospital Sant Pau, Barcelona
[email protected]
Nilesh Gandhi
Gandhi Onco Care
[email protected]
Sergi Castellvi-Bel
IDIBAPS
[email protected]
Aydin Demiray
Pamukkale University
[email protected]
Alba Garcia
UAB
[email protected]
Mercedes Castillo
University of Bonn
[email protected]
Gaurav Dular
Dular & Weiner
[email protected]
Silvia Garcia Roman
Pangaea Biotech
[email protected]
Webster Cavanee
UCSD
[email protected]
Gabrijela Dumbovic
IMPPC
[email protected]
Mireia Gausachs Romero
ICO-IDIBELL
[email protected]
María Virtudes Céspedes
IIB Sant Pau. Hospital de Sant
Pau
[email protected]
Miquel Duran-Frigola
IRB Barcelona
miquel.duran@irbbarcelona.
org
Sabrina Giampaolo
Università degli studi di Parma
sabrina.giampaolo@studenti.
unipr.it
Imane Chaib
ICO
[email protected]
Harvey Evans
IMPPC
Ana Gimenez Capitan
Pangaea Biotech
agimenez@pangaeabiotech.
com
Emili Cid
Josep Carreras Institute
[email protected]
Adrià Closa Mosquera
IDIBELL
[email protected]
[email protected]
Eduard Eyras
UPF - ICREA
[email protected]
Pepita Giménez-Bonafé
University of Barcelona
[email protected]
Eudald Felip Falgas
Hospital Germans Trias i Pujol
[email protected]
Antonio Gómez
PEBCWWIDIBELL
[email protected]
93
Santi Gonzalez
BSC
[email protected]
Beatriz Gonzalez Alonso
IMPPC
[email protected]
Maria Gonzalez Cao
Dexeus-Quiron Barcelona
[email protected]
Xavier Gonzalez Farre
Instituto oncologico Dr Rosell
[email protected]
Gloria Gonzàlez Gacio
BITAC MAP S.L
[email protected]
Cristina Gonzalez Julian
MU Pleven
[email protected]
Miguel Angel Gonzalez Labasa
Hospital San Pedro de la Rioja
[email protected]
Armand Gutierrez
UPF / IMIM
[email protected]
Sara Gutierrez-Enriquez
VHIO
[email protected]
Curtis C Harris
NCI
[email protected]
Carles Hernandez-Ferrer
CREAL
[email protected]
Marta Hidalgo Garcia
Centro de Investigación Príncipe Felipe, CIPF
[email protected]
Francia Holguín Flores
ICO Girona
[email protected]
Petra Hyrossova
University of Barcelona
[email protected]
CONTACTS
Ana Igea
IRB Barcelona
[email protected]
Laura Isus
IRB Barcelona
[email protected]
David Izquierdo Fontanills
UAB
[email protected]
Samira Jaeger
IRB Barcelon
samira.jaeger@irbbarcelona.
org
Eloisa Jantus Lewintre
Hospital General de Valenci
[email protected]
Eloisa Jantus-Lewintre
Hospital General de Valencia
[email protected]
Toni Jauset
VHIO
[email protected]
Teresa Juan-Blanco
IRB Barcelona
[email protected]
Candido Juarez
Hospital Sant Pau, Barcelona
[email protected]
Niki Karachaliou
Dr Rosell Oncology Institute
[email protected]
Nedim Karagenc
Pamukkale Univetsity
[email protected]
Ege Riza Karagur
Pamukkale University
[email protected]
Fuyumi Kato
IMPPC
[email protected]
Takaharu Kato
IMPPC
[email protected]
Takashi Kohno
NCCRI
[email protected]
Hakan Kucuksayan
Pamukkale University
[email protected]
Arànzazu Lafuente Sanchis
Hospital Universitario de la
Ribera
[email protected]
Conxi Lazaro
ICO
[email protected]
Kira Làzaro Morató
ICO
[email protected]
Ettore Luzi
University of Firenze
[email protected]
Andrea Malfettone
IDIBELL
[email protected]
Anna Manzano Cuesta
University of Barcelona
[email protected]
Irene Marchesi
IMPPC
[email protected]
Miguel Marín Rodero
UAB
miguel.marin.rodero@gmail.
com
Alicia Marsa Salvany
UAB
[email protected]
Agueda Martinez Barriocanal
VHIO
[email protected]
Eva Martinez-Balibrea
ICO
[email protected]
Laura Martinez-Martinez
Hospital Sant Pau, Barcelona
[email protected]
Lidia Mateo Ramos
IRB Barcelona
[email protected]
Ruth Muñoz Risueño
Josep Carreras Institute
[email protected]
Pol PiqueGermans
Trias Institute (IGTP)
[email protected]
Pedro Medina
Genyo
[email protected]
Pilar Mur
ICO, IDIBELL
[email protected]
Merce Planas-Felix
BSC
[email protected]
Edwin Mejía
Hospital Germans Trias i Pujol
[email protected]
Lada Murcia
IRB Barcelona
[email protected]
Raquel Pluvinet Ortega
IMPPC
[email protected]
Gironella Cos Meritxell
Hospital Clinic Barcelona/
CIBERehd
meritxell.gironella@ciberehd.
org
Ernest Nadal
ICO
[email protected]
Cristian Polo
IMPPC
[email protected]
Juan Nieto
IIB Sant Pau. Hospital de Sant
Pau
[email protected]
Miriam Potrony
Hospital Clinic Barcelona IDIBAPS
[email protected]
Ma Angels OrtizIIB
Sant Pau. Hospital de Sant Pau
[email protected]
Ester Pozas
IDIBAPS
[email protected]
Monica Pascual-Garcia
IIB Sant Pau.F Hospital de
Sant Pau
[email protected]
Aleix Prat
Hospital Clinic, Barcelona
[email protected]
Jordi Minguillón Pedreño
UAB
[email protected]
Gemma Montalban Canudas
VHIO
[email protected]
Helena Montanuy Escribano
UAB
helena_montanuy@hotmail.
com
Daniela Morales-Espinosa
Instituto Oncológico Dr Rosell
[email protected]
Mireia Morell Ginestà
ICO
[email protected]
Juan Moreno Felici
University of Barcelona
[email protected]
Roberto Mosca
IRB Barcelona
roberto.mosca@irbbarcelona.
org
Loris Mularoni
UPF
[email protected]
Marta Munar
BSC
[email protected]
Miguel A Peinado
IMPPC
[email protected]
Ines Perea
Astra Zeneca
[email protected]
Lídia Perea Soriano
IIB Sant Pau. Hospital de Sant
Pau
[email protected]
Jana Peremarti Brosel
UAB
[email protected]
Manuel Perucho
IMPPC
[email protected]
Marta Pineda Riu
ICO
[email protected]
Janet Pinero
Hospital del Mar, Barcelona
[email protected]
Pablo Prieto Barja
CRG
[email protected]
Joan Anton Puig Butille
Hospital Clinic Barcelona
[email protected]
Raimon Puig de la Bellacasa
IQS
[email protected]
Roser Pujol
UAB
[email protected]
Laia Ramos Masdeu
IMPPC
[email protected]
Maria Angels Rigoa Tor
UAB
[email protected]
Pere Roca-Cusachs
Institute for Bioengineering of
Catalonia
[email protected]
95
Ana Rodriguez Garcia
University of Barcelona
[email protected]
Montse Sanchez-Céspedes
IDIBELL
[email protected]
Sonia Sole Sanchez
IMPPC
[email protected]
Bernardo Rodríguez Martín
BSC
[email protected]
Inigo Santamaria Ruiz de Azua
HUCA/IUOPA
[email protected]
Martin Sos
University of Cologne
[email protected]
Rosa Romero
VHIR
[email protected]
Sheila Santin
IMPPC
[email protected]
Laura Soucek
VHIO
[email protected]
Rafael Rosell
ICO
[email protected]
Celia Santos Tapia
IRB Barcelona
[email protected]
Laura Rubio
UAB
[email protected]
Martin Schaefer
CRG
[email protected]
Wafa Soudani
Chemistry Laboratory Therapeutic
[email protected]
Carlota Rubio-Perez
UPF
[email protected]
Endre Sebestyén
GRIB
[email protected]
Carolina Ruivo Pereira
PEBC - IDIBELL
[email protected]
Sandra Segura Bayona
IRB Barcelona
sandra.segura@irbbarcelona.
org
Anna Ruiz Nel·lo
Hospital de Sabadell
[email protected]
Lucas Salas Diaz
CREAL
[email protected]
Ramon Salazar
ICO
[email protected]
Paula Samsó Ferré
University of Barcelona
[email protected]
Johanna Samuelsson
Active Motif
[email protected]
Javier Sanchez
Astra Zeneca
javier.sanchez@astrazeneca.
com
Mayka Sanchez
IMPPC
[email protected]
CONTACTS
Sigrid Segura Roca
IMIM
[email protected]
Alice Serafin
University of Bologna
[email protected]
Eduard Serra
IMPPC
[email protected]
David Shan
BGI Europe
[email protected]
Helga Simon Molas
University of Barcelona
[email protected]
Egbert Smit
VU University
[email protected]
Francesc Sole
Josep Carreras Institute
[email protected]
Jitka Soukupova
IDIBELL
[email protected]
Elisabetta Stanzani
University of Barcelona IDIBELL
[email protected]
Mónica Suelves
IMPPC
[email protected]
Lauro Sumoy
IMPPC
[email protected]
Ida Tateo
Novartis
[email protected]
Cristina Teixido
Pangaea Biotech SL
[email protected]
Gemma Tell Marti
IDIBAPS - Hospital Clinic
Barcelona
[email protected]
Ernest Terribas Pérez
IMPPC
[email protected]
Onur Tokgun
IMPPC
[email protected]
Marta Tomas
DNAfB
[email protected]
Robert Torka
MPIB
[email protected]
Santiago Viteri
Quiron Dexeus
[email protected]
Davis Torrejon
VHIO
[email protected]
Kristiina Vuori
SBMRI
[email protected]
David Torrents
BSC
[email protected]
Aiden Whitty
Thomson Reuters
aiden.whitty@thomsonreuters.
com
Avelina Tortosa
University of Barcelona
[email protected]
Laura Valle
ICO, IDIBELL
[email protected]
Gardenia Vargas Parra
ICO-IDIBELL
[email protected]
Tanya Vavouri
Josep Carreras Institute
[email protected]
Silvestre Vicent
CIMA
[email protected]
Silvia Vidal
IIB Sant Pau. Hospital de Sant
Pau
[email protected]
Fumi Yamamoto
IMPPC
[email protected]
Miyako Yamamoto
IMPPC
[email protected]
Jun Yokotoa
IMPPC
[email protected]
Luis Zapata
CRG
[email protected]
Roser Zaurin Quer
Institut de Biomedicina i Biotecnologia
[email protected]
Adrià Vidal
Josep Carreras Institute
[email protected]
Anna Vidal-Alabró
University of Barcelona
[email protected]
Maria Vila Casadesus
IDIBAPS
[email protected]
Laura Vila Vecilla
UAB
[email protected]
Natàlia Vilor Tejedor
CREAL
[email protected]
97
CONTACTS IMPPC
For further information on the IMPPC please write to:
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Molecular Targets for Predictive and Personalized Medicine of Cancer
6th Annual IMPPC Conference
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