Re-use of established drugs for anti-metastatic indications Prof. Dr

Re-use of established drugs for anti-metastatic indications Prof. Dr

Re-use of established drugs for anti-metastatic indications
Prof. Dr. rer. nat. habil. Frank Entschladen
- Chief Science Officer –
MetaVì Labs
Leukocytes: Immune response
Stem cells:
Tissue regeneration
Cell Migration
Tumor cells: Invasion and metastasis
Fibroblasts:
Wound healing
Why is measuring cell migration in cancer so valuable?
Invasion and Metastasis
nervous system lymph nodes lymphogenic metastases distant metastases perineural invasion liver lung bone marrow T
DC
NG MΦ
primary tumor hematogenic metastases Rationale and market need
“It is local invasion and distant metastasis that kill rather
than excessive cell proliferation per se.”
Michael B. Sporn “The war on cancer.”
1996, Lancet
over 90% of cancer deaths are due to metastasis
there is currently no anti-metastatic drug available
tumor cell migration is an essential prerequisite for
invasion and metastasis
“Until non-clinical models with good predictive properties
have been defined… the absence of such models is
considered to constitute the greatest hurdle for efficient drug
development within the foreseeable future.”
European Medicines Agency, Oncology Working Party
“Guideline on the evaluation of anticancer medicinal products in man”
2011, EMA/CHMP/205/95/rev. 4
“A better understanding of the mechanisms of cell motility and
cytoskeletal regulation may provide novel therapeutic
strategies that would block metastatic progression, reducing
dissemination of tumor cells and increasing patient survival.”
Dmitriy Kedrin, Jacco van Rheenen, Lorena Hernandez, John Condeelis, Jeffrey E. Segall
“Cell motility and cytoskeletal regulation in invasion and metastasis”
2007, J Mammary Gland Biol Neoplasia
Growth Factors Extracellular Matrix Neurotransmi<ers Chemokines G Protein-­‐Coupled Receptors (GPCRs) Cadherins α
p120 α
β
γ
GRK β-­‐Catenin Receptor Tyrosine Kinases (RTKs) β-­‐ArresFn srcPTK PLCγ
PLB SERCA Calcium PKA Rap1 AF6 PI3K
IP3+DAG cAMP EPAC
PIP2 Vin PIP3 PIP2 Grb2
Ras
Raf
MEK1/2
ERK1/2
Sos
PDK
PKC
AcFn Paxillin FAK
AcFn GSK3β
Integrins Talin Shc
α-­‐Catenin AC α
Grb2
srcPTK ATP β
EndoplasmaFc ReFculum KRIT AcFn Calcium GDI Tiam Vav2 Akt/PKB
CaM/MLCK Calcium GEF MARCKS p130CAS PAK
Cdc 42 ENA/ VASP Rho ROCK Rac
Crk
MLC PIP2 Non-­‐muscle Myosin II AcFn AcFn WAVE
WASP
Calcium Gelsolin AcFn PIP2 Profilin Arp2/3 complex
AcFn Schaap-Nutt et al. Curr. Pharm. Des., 2014
Beta-Blockers
in vitro
mouse model
patient studies
p=0.022 metastasis primary tumor p=0.013 Growth Factors Extracellular Matrix Neurotransmi<ers Chemokines G Protein-­‐Coupled Receptors (GPCRs) Cadherins α
p120 α
β
γ
GRK β-­‐Catenin Receptor Tyrosine Kinases (RTKs) β-­‐ArresFn srcPTK PLCγ
PLB SERCA Calcium PKA Rap1 AF6 PI3K
IP3+DAG cAMP EPAC
PIP2 Vin PIP3 PIP2 Grb2
Ras
Raf
MEK1/2
ERK1/2
Sos
PDK
PKC
AcFn Paxillin FAK
AcFn GSK3β
Integrins Talin Shc
α-­‐Catenin AC α
Grb2
srcPTK ATP β
EndoplasmaFc ReFculum KRIT AcFn Calcium GDI Tiam Vav2 Akt/PKB
CaM/MLCK Calcium GEF MARCKS p130CAS PAK
Cdc 42 ENA/ VASP Rho ROCK Rac
Crk
MLC PIP2 Non-­‐muscle Myosin II AcFn AcFn WAVE
WASP
Calcium Gelsolin AcFn PIP2 Profilin Arp2/3 complex
AcFn Schaap-Nutt et al. Curr. Pharm. Des., 2014
Pharma-pipelines: Receptor Tyrosine Kinases
Target
EGFR
EGFR/HER2
HER2
HER3
c-Met
FGFR
multi-RTK
Substance name
Company
ABT-806
Abbott
Panitumumab
Amgen
Erlotinib
Astellas
Gefitinib, Vandetanib
AstraZeneca
Cetuximab
Bristol-Myers Squibb
Nimotuzumab
Daiichi-Sankyo
Necitumumab
Eli Lilly
Matuzumab
EMD Serono
Erlotinib
Merck
Afatinib
Boehringer Ingelheim
Dacomitinib
Pfizer
TAK-165
Takeda
Patritumab
Daiichi-Sankyo
LJM716
Novartis
RG7116
Roche
SAR256212
Sanofi-Aventis
ABT-700
Abbott
AMG208, AMG337
Amgen
Tivantinib
Daiichi-Sankyo
LY2875358
Eli Lilly
GSK1363089
GlaxoSmithKline
JNJ38877605
Johnson&Johnson
MK2461, MK8033
Merck
AZD4547
AstraZeneca
LY2874455
Eli Lilly
BGJ398
Novartis
ABT-348
Abbott
Regorafenib
Bayer
Nintedanib
Boehringer Ingelheim
JNJ26483327
Johnson&Johnson
Axitinib, Sunitinib
Pfizer
Schaap-Nutt et al. Curr. Pharm. Des., 2014
Regorafenib
Growth Factors Extracellular Matrix Neurotransmi<ers Chemokines G Protein-­‐Coupled Receptors (GPCRs) Cadherins α
p120 α
β
γ
GRK β-­‐Catenin Receptor Tyrosine Kinases (RTKs) β-­‐ArresFn srcPTK PLCγ
PLB SERCA Calcium PKA Rap1 AF6 PI3K
IP3+DAG cAMP EPAC
PIP2 Vin PIP3 PIP2 Grb2
Ras
Raf
MEK1/2
ERK1/2
Sos
PDK
PKC
AcFn Paxillin FAK
AcFn GSK3β
Integrins Talin Shc
α-­‐Catenin AC α
Grb2
srcPTK ATP β
EndoplasmaFc ReFculum KRIT AcFn Calcium GDI Tiam Vav2 Akt/PKB
CaM/MLCK Calcium GEF MARCKS p130CAS PAK
Cdc 42 ENA/ VASP Rho ROCK Rac
Crk
MLC PIP2 Non-­‐muscle Myosin II AcFn AcFn WAVE
WASP
Calcium Gelsolin AcFn PIP2 Profilin Arp2/3 complex
AcFn Schaap-Nutt et al. Curr. Pharm. Des., 2014
Pharma-pipelines: Signal Transduction
Target
Substance name
GSK2141795, GSK2110183,
Akt
src
FAK
PI3K
GSK690693
Company
GlaxoSmithKline
Target
Substance name
Company
b-raf
GSK2118436
GlaxoSmithKline
pan-raf
MLN2480
Takeda/Millenium
MK-2206
Merck
Refametinib
Bayer
RG7440
Roche
BI847325
Boehringer Ingelheim
Bosutinib
Pfizer
Primasertib
EMD Serono
GSK1120212
GlaxoSmithKline
MEK
BI853520
Boehringer Ingelheim
GSK2256098
GlaxoSmithKline
RG7167, RG7304, RG7420
Roche
VS-6063, VS-4718
Verastem
TAK-733
Takeda
AMG319
Amgen
Momelotinib
Sciences
SAR302503
Sanofi-Aventis
MT103
Medisyn Technologies
AEB071
Novartis
BAY80-6946
Bayer
DS-7423
Daiichi-Sankyo
Idelalisib, GS-9820
Sciences
GSK2636771, GSK2126458
GlaxoSmithKline
BEZ235, Buparlisib, BYL719
Novartis
PF-04691502, PF-05212348
Pfizer
CHU
Roche
SAR245408, SAR245409
Sanofi-Aventis
MLN1117
Takeda/Millenium
VS-5584
Verastem
JAK
PKC
Schaap-Nutt et al. Curr. Pharm. Des., 2014
Buparlisib (BKM120)