CUDC-907 - Curis Inc.

DUAL FUNCTION HDAC AND PI3K INHIBITOR CUDC-907 AFFECTS CANCER CELLS AND THE TUMOR MICROENVIRONMENT IN HEMATOLOGICAL MALIGNANCIES
Inc., Lexington, MA; 2Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Sarah Cannon Research Institute, Nashville, TN; 4Lymphoma and Myeloma Department, M.D. Anderson Cancer Center, Houston, TX * These authors contributed equally
Introduction
Ac-H3
pPRAS40
pS6
CUDC-907 100mpk
5th Dose, QD
Note: C57BL/6 mice
were dosed with
CUDC-907 or control
vehicle for 5 days
through daily oral
administration.
Marrow of femur bone
was isolated for IHC.
Red arrows indicate
megakarocytes.
CUDC-907 Decreases TARC Levels
in a Hodgkin’s Lymphoma Cell Line
IC50 (nM)
Alpha
Delta
Beta
Gamma
19
39
54
311
1
10
100
Tubulin
CUDC-907 Decreases TARC Levels
in a DLBCL Cell Line
RTK
CUDC-907+M2:
LBH-589:
GDC-0941:
L+G:
D
CUDC-907+M2
M2
LBH-589
DMSO
L+G
GDC-0941
10
LBH-589
1
Ctrl
10
GDC-0941
1
Ctrl
L+G
10
1
Ctrl
10
1
(µM)
pSTAT6
Patient Plasma TARC Level
Changes in Phase I Clinical Trial
E
CUDC-907+M2
10
LBH-589
1
Ctrl
10
GDC-0941
1
Ctrl
10
A
L+G
1
Ctrl
10
1
C
pSTAT6
Note: A&B. RPMI-8226 multiple myeloma cells were incubated with indicated compounds for
24 hours. Cells were collected for RT-PCR analysis (A), and culture media were collected for
TARC ELISA (B). Data are normalized against DMSO control. C. Dosing method used in the
washout experiments (D&E) to mimic clinical exposure. D. RPMI-8226 cells were treated with
indicated compounds as in C for a total of 24 hours prior to Western blot analysis. E. OPM-2
cells were treated with indicated compounds as in C for a total of 42 hours prior to Western
blot analysis. CAL-101: PI3Kδ inhibitor; L+G: LBH-589 + GDC-0941.
Proliferation & Survival
Note: GDC-0941 is a pan PI3K inhibitor; LBH-589 and SAHA are both pan HDAC inhibitors
Tubulin
Note: DOHH2 DLBCL cells were incubated with indicated compounds for 24 hours prior to
Western blot analysis. L+G: LBH-589+GDC-0941
CUDC-907
CAL-101
CUDC-907
CAL-101
CUDC-907
0.1
1
10
Ctrl
0.001
0.01
0.1
1
Ctrl
0.1
1
10
0.001
0.01
0.1
1
Ctrl
0.1
1
10
Ctrl
10
100
TARC
(µM)
(µM)
CAL-101
Note: Human CD4+ T-cells stimulated with anti-CD3 & anti-CD28 antibodies for 31 hours were
treated with indicated compounds for 16 hours prior to RT-PCR and cell viability testing.
Culture media were collected for soluble CD40 ligand ELISA. CD4+ cells from healthy donors
were from a commercial source.
CUDC-907
Note: CUDC-907 decreases the production of CD40 ligand by CD4+ T cells. It also decreases
the STAT6 phosphorylation-medicated TARC production by the HRS Hodgkin’s lymphoma
cells. TARC stimulates the proliferation, maturation, and migration of T helper 2 cells, which is
important for the survival of malignant B cells. CUDC-907 also decreases other cytokines and
chemokines in primary CLL and NLC co-cultures. HRS: Hodgkin and Reed-Sternberg (HRS)
cell of classical Hodgkin's lymphoma; NLC: monocyte-derived nurselike cell; MSC:
mesenchymal stromal cell.
Conclusion
 CUDC-907 inhibits STAT6-mediated TARC production in
Hodgkin's lymphoma, DLBCL, and multiple myeloma cell lines
B
D
 CUDC-907 decreases CD40L production in stimulated human
primary CD4+ T-Cells
 CUDC-907 is able to overcome stromal cell-protection of primary
CLL cells in in vitro co-culture system, where treatment of
CUDC-907 decrease cytokine and chemokine levels.
CUDC-907 Decreases CD40L
Production in Stimulated CD4+ T-Cells
(µM)
NLC
 In this study, PI3K and HDAC inhibition by CUDC-907 has
been demonstrated in vivo in mouse bone marrow
Tubulin
(nM)
S6K
MSC
 CUDC-907 decreases the activity of multiple pathways, such as
PI3K/AKT, MEK/ERK, and JAK/STAT pathways due to dual PI3K
and HDAC inhibition
(µM)
 The ongoing first-in-human Phase 1 trial testing CUDC-907 in
the setting of advanced lymphoma and multiple myeloma has
yielded preliminary evidence of anti-cancer activity and potential
impact on the tumor microenvironment
E
pSTAT6
ERK
Note: A. Primary CLL cells cultured with or without human PBMC-derived nurse-like cells
(NLC) were incubated with indicated compounds for 24 hours prior to cell viability assay.
Data are normalized against DMSO control. B. Primary CLL cells and NLC cells were
cultured alone or together, and treated with 1000 nM of CUDC-907 or LBH-589 for 24 hours.
Culture medium was collected for MSD multiplex cytokine and chemokine ELISA assays.
Primary CLL cells were from a commercial source.
GDC-0941
CUDC-907+M2
Ctrl
HRS
L+G
1000
1
10
100
Tubulin
1000
Tubulin
GDC-0941
1
ERK
10
p-4EBP1
mTOR
100
p-ERK
AKT
1000
p-Akt
Tubulin
MEK
LBH-589
1
STAT3
STAT
10
(Y705)
M2
100
p-STAT3
Tubulin
CUDC-907
PTEN
RAF
(S727)
CXCL-12
CXCL-13
JAK1/3
PI3K
1000
p-STAT3
RAS
1
JAK
10
CUDC-907
SAHA
LBH-589
GDC-0941
Ctrl
CUDC-907
LBH-589
GDC-0941
RPMI8226 (MM)
16hr 1µM
Ctrl
CUDC-907
Note: L428 Hodgkin’s Lymphoma cells were incubated with indicated compounds for 16 hours
prior to Western blot analysis. L+G: LBH-589+GDC-0941
100
• ~ 80% PI3K activity as
compared to parent
• No HDAC activity
1000
• ~ 30% PI3K activity as
compared to parent
• No HDAC activity
CCL3
CCL4
Long-term incubation
STAT3
R
M2
LBH-589
Western blot
sample collection
pSTAT3
TARC
M1
CD40
LBH-589 CAL-101
TARC
R
H N
2
LBH-589
Ac-Tub
1
R
Malignant
B Cell
STAT6
Ctrl
pSTAT6
R
R
p53
M2
(nM)
O
bRaf
CUDC-907
pPRAS40
Ctrl
Ac-p53
GDC-0941
Ctrl
Ac-Tub
LBH-589 CAL-101
Washout &
re-dosing
1-hr incubation
0.001
O
p-bRaf
M2
Tubulin
Cl Caspase3
Ac-H3
C
0.01
• Full HDAC activity
• Full PI3K activity
Daudi (DLBCL)
16hr 1µM
CUDC-907
IL-13
TARC
(nM)
CUDC-907
0.1
PI3Ki Moiety
CUDC-907
HO
(nM)
L+G
1000
1
10
100
1000
LBH-589
1
10
100
1000
1
GDC-0941
10
100
1000
M2
1
10
100
M1
1000
1
10
Ctrl
CUDC-907
Caspase3
R
(nM)
R
R
HDACi Moiety
PI3K
CUDC-907
1
R
IL-4
TNF-α
CCL3&4
CXCL-12
IL-6
Ctrl
1.7
5.0
1.8
27
2.8
>200
B
CD40L
Akt
1
2
3
6
10
4, 5, 7, 8, 9
A
B
CUDC-907 Targets Tumor
Microenvironment
CD4+
T Cell
pAkt
IC50 (nM)
Primary CLL Cells Are Sensitive to
CUDC-907
TARC
CUDC-907 Disrupts Key RTK
Signaling Pathways
HDAC
CUDC-907 Inhibits TARC Production in
Multiple Myeloma Cell Lines
A
Control Vehicle
5th Dose, QD
Histone deacetylases (HDACs) and the phosphatidylinositol 3kinase (PI3K)/AKT pathways are promising therapeutic targets
in hematologic cancers and evidence of synergistic anti-cancer
activity has recently emerged. CUDC-907, a small molecule
drug candidate that is designed to target HDACs and PI3Ks in a
single chemical entity, is currently in Phase 1 clinical testing for
the treatment of patients with lymphoma or multiple myeloma.
Preclinically, CUDC-907 has been shown to inhibit activation of
PI3K/AKT, JAK/STAT and MAPK pathways in solid tumor and
hematologic cancer cell lines. In this study, we report that in the
setting of hematologic malignancies, CUDC-907 targets not
only the cancer cells but also the tumor microenvironment. In
the ongoing clinical study, we monitor a panel of 12 cytokines
and chemokines. Preliminary results indicate correlative trends
between tumor response and baseline TARC levels, and
between tumor response and plasma TARC level changes after
15 days of treatments. Based on these results, we are further
investigating the potential of utilizing select cytokines and
chemokines as predictive markers of CUDC-907 activity.
CUDC-907 Inhibits PI3K & HDAC
Activities in Mouse Bone Marrow
100
1Curis,
1000
#1879
Anna W. Ma1*, Ruzanna Atoyan1*, Anas Younes2, Ian W. Flinn3, Yasuhiro Oki4, Amanda Copeland2, Jesus G Berdeja3, Robert Laliberte1, Jaye Viner1, Maria-Elena S. Samson1, Ze Tian1, Steven
Dellarocca1, Ling Yin1, Mylissa Borek1, Brian Zifcak1, Guangxin Xu1, Jing Wang1
Correlation Between Tumor Response and Plasma TARC Levels (N=11)
Patient Plasma
TARC
P value (two-tailed)
R square
Day 15 Percentage
Day 15 Absolute
Baseline
Change
Concentration Change Concentration
0.082
0.203
0.095
0.298
0.173
0.279
Note: A&B. Clinical tumor response vs. day 15 plasma TARC level changes in CUDC-907
phase I trial. C&D. Clinical tumor response vs. baseline plasma TARC levels. E. Trend of
correlation between plasma TARC level and Best tumor response, (N=11).
 These results suggest the potential utility of selected cytokines
and chemokines as predictive markers of CUDC-907 activity
AACR 2014, San Diego, CA; Poster # 1879
This study is sponsored by Curis, Inc. with financial
support from the Leukemia & Lymphoma Society.