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ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.
THE CANCER STEM CELL INHIBITORS VS-6063 AND VS-5584 EXHIBIT SYNERGISTIC ANTICANCER
ACTIVITY IN PRECLINICAL MODELS OF MESOTHELIOMA
Mitchell Keegan, Ph.D.Vice President of Development, Verastem, Inc.
1
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.2
Disclosure
• I am an employee and stockholder of Verastem Inc.
• I will be discussing investigational drugs
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.3
Developing potential treatment options throughout the mesothelioma patient journey
Treatment holiday4‐6 cycles Pem/Cis
Surgery
80%
20%
MPM
Neo‐adjuvant VS‐6063+VS‐5584Relapsed
Ongoing studies:
2nd line chemo or clinical trial
We want to maximize the potential treatment options for patients with mesothelioma
VS‐6063 VS‐6063
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.4
Standard‐of‐care chemotherapy enriches cancer stem cells in both mesothelioma cell lines and patient tumors
Mesothelioma CSCs in vitroH2052 cell line
Mesothelioma CSCs in vivoPaired patient biopsies
Pre‐treatment Post‐treatment
Brown = ALDH+ (cancer stem cells)
MPM cells treated with SOC chemotherapies are enriched for
cancer stem cells
Pem/Cis
Treatment of MPM tumors with SOC chemotherapy enriches for cancer stem cells
Pre Post
Mean H Score / Patient
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.5
Profiles of VS‐6063 & VS‐5584
• Potent, selective inhibitor of FAK & PYK2 tyrosine kinases
• Preferentially targets Cancer Stem Cells (CSCs)
• Lead compound, studied in 300+ patients to date with good safety profile
• Ongoing registration‐directed trial in mesothelioma
• Orphan designation in US and EU for mesothelioma
• Potent, selective inhibitor of PI3K & mTOR kinases
• Preferentially targets Cancer Stem Cells (CSCs)
• Currently in Phase 1 with intermittent dosing schedule (3x weekly)
FAK EC50 = 15 nMPYK2 EC50 = 95 nM
VS‐6063 (defactinib) VS‐5584
PI3K
AKT
mTORC2
AKTVS‐5584
RTKs
mTORC1
Tumor cell/CSC survival & proliferation
mTORIC50 (nM)
PI3K isoform IC50 (nM)
α β δ γ
3.4 2.6 21 3.0 2.7
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.6
Rationale: Combination of VS‐6063 (FAK) with VS‐5584 (PI3K/mTOR) for the treatment of relapsed/refractory mesothelioma
• 29 patients evaluated by GSK with their FAK inhibitor in Phase 1: Treatment resulted in median PFS of 4.5 months (vs. 6 weeks)
• 1 patient in VS‐6063 Phase 1 in Japanese subjects: Symptom improvement and PFS of 5.6 months
• PI3K/mTOR dual inhibitor GDC‐0980 showed 4 PRs among 33 mesothelioma patients in a Phase 1 study (ECCO 2013)
Both FAK & PI3K/mTOR inhibitors have shown early signs of clinical activity in mesothelioma
FAK & PI3K/mTOR inhibition may combine for more robust shut down of AKT survival signaling
Y397FAKSRC
IntegrinRTKs
Proliferation/Survival/CSC Function
mTORC1
PI3K
mTORC2 p130Cas
PAkt
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.7
VS‐6063 inhibits tumor initiation in mouse mesothelioma models
0
20
40
60
80
100
120
0 1 2 4 5 6 7 8 9 10
Tumor free
mice, %
Weeks
Control
Pemetrexed
VS‐6063
VS‐6063 + Pem
Control
VS‐6063
PemetrexedRecovery
H28 meso cell line
Tumor initiation in vivo
VS‐6063 &Pemetrexed
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.8
Oral administration of VS‐6063 targets cancer stem cells in mesothelioma tumors grown in mouse lungs
DAPICancer Stem Cells (ALDH+)
Control VS‐6063
* p<0.05
50 mg/kg, po BID x 2 wks
VS‐6063 treatment, MM87 mesothelioma xenograft model:
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.9
VS‐5584 preferentially targets CSCs: ~ 70‐fold reduction in tumor initiating frequency in a SCLC model
VS‐5584 treatment, H841 SCLC model:
Liberase
Viable cells Re‐implantation in limiting dilutions
CSC Assays
Tumor Initiation
****
Antitumor Efficacy SP CSC Assay
0
10
20
30
40
50
Vehicle VS‐5584
Tumor In
itiating
Cells / 1 million
p < 0.0001
Control
VS‐5584
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.10
VS‐5584 & VS‐6063 exhibit synergistic combination activity in mesothelioma cell lines in vitro
Highest Single Agent Analysis
0.0
0.5
1.0
1.5
2.0
Combina
tion Inde
x
VS‐6063 + VS‐5584Mero‐41 mesothelioma
ED50 ED75 ED90
10.000 0.00 0.00 0.09 0.06 0.07 0.25 0.09 0.04 0.04
3.333 0.00 0.06 ‐0.01 0.07 0.08 0.23 0.08 0.05 0.04
1.111 0.00 ‐0.01 0.09 0.08 0.17 0.22 0.04 0.05 0.04
0.370 0.00 0.03 0.10 0.15 0.24 0.10 0.04 0.03 0.02
0.123 0.00 0.08 0.11 0.17 0.12 0.12 0.02 0.01 0.01
0.041 0.00 ‐0.07 0.07 0.10 0.09 0.13 0.01 0.01 0.01
0.014 0.00 ‐0.05 ‐0.08 0.20 0.15 0.08 0.00 0.00 0.01
0.005 0.00 ‐0.14 0.05 ‐0.10 0.05 ‐0.03 0.00 ‐0.01 0.01
0.002 0.00 ‐0.05 ‐0.10 0.07 ‐0.08 0.03 0.00 0.01 0.01
0.000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
0.001 0.002 0.005 0.014 0.041 0.123 0.370 1.111 3.333
Synergy
VS‐5584
VS‐606
3
0.0
0.5
1.0
1.5
2.0
.
Combina
tion Inde
x
VS‐6063 + VS‐5584H2052 mesothelioma
ED50 ED75 ED90
0.001 0.01 0.1 1 100.0
0.2
0.4
0.6
0.8
1.0
M
Combination Index AnalysisAn
tagonism
Syne
rgism
HSA Additivity ModelVS‐6063 VS‐6063 + VS‐5584
VS‐5584 + VS‐6063 @ 0.41 µMVS‐5584 + VS‐6063 @ 1.11 µM
Antagonism
Syne
rgism
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.11
Synergistic combination of VS‐5584 and VS‐6063 for targeting tumor initiating cells
Control
VS‐6063
VS‐5584Recovery
Meso cell line Limiting dilutions assayVS‐5584 & VS‐6063
1
10
100
1000
10000
Control VS‐5584 VS‐6063 VS‐5584 &VS‐6063
TIC pe
r 106
cells
150‐folddecrease
196‐folddecrease
∞decrease
Limiting dilution tumor initiation
Aldefluor assay
H28 cell line
Alde
fluor+ CSCs
(% of C
ontrol)
Aldefluor+ CSCsMero‐14 cell line
0.1 µM 0.3 µM
VS‐6063VS‐5584Combo
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.12
Synergistic combination of VS‐5584 and VS‐6063 for enhanced anti‐tumor efficacy compared to single agent in orthotopic meso model
0
20
40
60
80
100
Control VS‐6063 VS ‐5584 VS‐6063 + VS‐5584
% of tum
or area
p < 0.0001
p < 0.0001
Injection
MM87 mesocell line Mesothelioma tumor
grown in lungs for 11 days
Control
VS‐6063 (BID)
VS‐5584 (M/W/F)
VS‐6063 & VS‐5584
Tumor burden
assessment
Treatment for 2 weeks
• 2 out of 10 mice tumor free in the VS‐6063 + VS‐5584 combination group
• No tumor free mice in other groups
Tumor burden after treatment
ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.13
Summary & conclusions
• VS‐6063 (defactinib) is a potent/selective FAK kinase inhibitor
• VS‐5584 is a potent/selective inhibitor of PI3K & mTORC1/2
• Both agents preferentially target CSCs and also reduce bulk tumor growth in preclinical mesothelioma models
• Synergistic activity of VS‐6063 & VS‐5584 on CSCs & bulk tumor has been observed in preclinical models
• These data support an ongoing Phase I combination study of VS‐6063 & VS‐5583 in patients with relapsed/refractory mesothelioma
– Additional study details will be presented at Poster #P2.08‐008