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Verastem Presents Data on Cancer Stem Cell-Targeting Agents at the 2014 AACR Annual Meeting
- Research Results Provide Additional Support for Targeting Cancer Stem Cells Directly and Through Immunomodulation of the Tumor Microenvironment –
“The data presented at AACR continue to expand our understanding of the
mechanisms of our compounds targeting cancer stem cells,” said
“These presentations continue to build upon a growing body of scientific
evidence supporting the development of VS-6063, VS-4718 and VS-5584,
which are potent inhibitors of cancer stem cells,” said
A summary of the data presented by
Oral Presentation
Title: VS-6063 (defactinib) targets cancer stem cells directly
and through inhibition of tumor-associated macrophages and cytokine
production
Date and time:
Location: Room 6B
Abstract Number:
4797
Session: Mini-symposium “Elucidation and Niche
Targeting of Cancer Stem Cell Epigenetic and Metabolic Alterations”
Summary:
Here we report that VS-6063 targets cancer stem cells directly and
through an immunomodulatory effect by reducing tumor-associated
macrophages. In addition to being a potent FAK inhibitor, study findings
have demonstrated that VS-6063 also inhibits the activity of PYK2, a
closely related protein kinase and only other member of the FAK family.
Several lines of evidence suggest that dual targeting of FAK and PYK2
should confer greater antitumor efficacy than inhibition of either
target alone. In PYK2 knockout mice, reduced macrophage infiltration has
been observed. Tumor-associated macrophages (TAMs) have been correlated
with poor prognosis in multiple cancer types, including mesothelioma and
breast cancer. The effects of PYK2 inhibition on TAMs were investigated
in the current study.
These research results demonstrated that VS-6063 directly kills CSCs through FAK inhibition. Interestingly, by inhibiting PYK2, VS-6063 also reduced the production of specific cytokines that are responsible for increasing cancer stem cells in mesothelioma and breast cancer in a dose dependent manner. A FAK-only reference inhibitor had no effect on these cytokines. Results also demonstrated that VS-6063 substantially reduced the number of TAMs in cancer xenograft models. The dual inhibition of FAK and PYK2 by VS-6063 effectively decreased CSCs directly, and both the presence of TAMs in tumors and the ability of TAMs to release cytokines that stimulate CSC proliferation and survival.
Poster Presentations
Title: Focal adhesion kinase (FAK) inhibitor VS-6063 (defactinib)
preferentially targets cancer stem cells in triple negative breast cancer
Date
and time:
Location:
Hall A-E
Abstract Number: 3908
Poster Section 2: Cancer
Stem Cell Phenotype, Function, and Targeting
Summary: Here
we report that VS-6063 potently targets, and abrogates
chemotherapy-induced enrichment of, cancer stem cells in models of
triple negative breast cancer. Triple negative breast cancer (TNBC) is
characterized by the lack of estrogen receptor (ER), progesterone
receptor (PR), and human epidermal growth factor receptor 2 (HER2) gene
expression, and comprises a heterogeneous group of breast cancers.
Amplification and overexpression of FAK have been observed in aggressive
human cancers, including breast cancer. In addition to regulating the
proliferation, survival, invasion and metastasis of cancer cells, FAK
also plays a critical role in the self-renewal and survival of CSCs.
CSCs have been shown to be resistant to standard chemotherapy and
associated with poor clinical outcomes.
These research results demonstrated that VS-6063 reduced the percentage of CSCs in human TNBC cells and reduced the proportion of CSCs in primary breast cancer tissue specimens cultured ex vivo. Standard of care agents (paclitaxel and doxorubicin) administered alone increased the percentage of CSCs suggesting these agents preferentially target bulk tumor cells. In contrast, when VS-6063 was administered in combination with the standard of care agent paclitaxel, VS-6063 attenuated the enrichment of chemotherapy-induced CSCs. Oral administration of VS-6063 resulted in a reduction of tumor CSCs in a human TNBC xenograft model in vivo. Collectively, these results indicate that VS-6063 preferentially targets CSCs in TNBC and supports the clinical development of VS-6063 in combination with standard of care agents to achieve more durable responses through the simultaneous targeting of both CSCs and bulk tumor cells.
Title: Combined inhibition of PI3K isoforms and mTOR kinase is
critical for cancer stem cell inhibition by VS-5584
Date and
time:
Location: Hall
A-E
Abstract Number: 3906
Poster Section 2: Cancer
Stem Cell Phenotype, Function, and Targeting
Summary: Here
we report that pan-inhibition of both mTOR and the PI3K isoforms by
VS-5584 is necessary for the effective targeting of cancer stem cells
and that single isoform inhibition does not lead to a cancer stem cell
preferential effect. VS-5584 is a highly potent dual inhibitor of
mTORC1/2 and PI3K that preferentially targets CSCs in vitro
and in vivo. VS-5584 has equipotency against all four human Class
I PI3K isoforms and the mTOR kinase.
These research results demonstrated that VS-5584 decreased CSCs across multiple cancer cell lines, including TNBC cells, while paclitaxel increased the proportion of cancer stem cells. In small cell lung cancer models (H69), VS-5584 effectively eliminated the CSC population, with a corresponding substantial delay in tumor regrowth following cisplatin treatment. Similarly, ex vivo treatment with VS-5584 preferentially reduced CSCs in primary tumor specimens from patients with breast cancer or ovarian cancer. Interestingly, knock down of PI3Kα, PI3Kβ or mTOR alone was insufficient to decrease CSCs, while knock down of PI3Kα, PI3Kβ and mTOR together effectively reduced CSCs mimicking the effect of VS-5584. These data help to elucidate the mechanism of VS-5584 targeting of CSCs and provide a strong rationale for the clinical development of VS-5584 in combination with chemotherapeutic agents targeting bulk tumor cells to achieve more durable clinical responses in cancer patients.
Title: VS-5584 a dual mTORC1/2 and PI3K inhibitor has anti-tumor
activity in multiple in vivo xenograft tumor models and enhanced
efficacy in combination with cisplatin or docetaxel
Date and
time:
Location: Hall
A-E
Abstract Number: 213
Poster Section 8: Stem
Cell Expansion and Cancer Stem Cell Targeting
Summary: Here
we report that intermittent dosing of VS-5584 is comparable to daily
dosing and has broad activity in models of multiple tumor types. In in
vitro assays, VS‐5584 has been shown to preferentially target
CSCs and exhibited significant anti-proliferative activity across
multiple cancer cell lines. Similarly, oral administration of VS-5584
has been shown to reduce CSCs in xenograft models. In this study, the in
vivo anti-tumor efficacy of once daily and intermittent oral
administration of VS-5584 was evaluated in several xenograft tumor
models in small cell lung cancer (SCLC), non-small cell lung cancer
(NSCLC), TNBC and mesothelioma.
These research results demonstrated that once daily treatment with VS-5584 resulted in potent and dose-dependent anti-tumor activity with mean percentage tumor growth inhibition (TGI) ranging from 40% to 97% (P<0.05), which was generally observed at well-tolerated dose levels. In evaluating intermittent dosing schedules, efficacy and tolerability were similar or better compared to continuous daily dosing. VS-5584 plus either cisplatin or docetaxel also showed a significant increase in TGI compared to cisplatin alone. The potent in vivo anti-tumor activity in xenograft models of SCLC, NSCLC, TNBC and mesothelioma suggests that VS-5584 has the potential for anticancer activity across a variety of cancer types. Importantly, intermittent dosing with VS-5584 was sufficient to achieve good efficacy while minimizing side effects, thus allowing a broader therapeutic window compared to daily dosing in these models.
About VS-6063
VS-6063 is an orally available compound designed to target cancer stem
cells through the potent inhibition of focal adhesion kinase (FAK).
Cancer stem cells are an underlying cause of tumor resistance to
chemotherapy, recurrence and ultimate disease progression. Research by
About VS-5584
VS-5584 is an orally available compound that has demonstrated potent and
highly selective activity against class 1 PI3K enzymes and dual
inhibitory actions against mTORC1 and mTORC2 pathways. In preclinical
studies, VS-5584 has been shown to reduce the percentage of cancer stem
cells and induce tumor regression in chemotherapy-resistant models.
About
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Company’s strategy, future plans and prospects, including statements
regarding the development of the Company’s compounds, the timeline for
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the expected timing for the reporting of data from ongoing trials, and
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clinical trials may not be predictive of the results or success of
ongoing or later clinical trials, that data may not be available when we
expect it to be, that the Company will be unable to successfully
complete the clinical development of its compounds, that the development
of the Company’s compounds will take longer or cost more than planned,
and that the Company’s compounds will not receive regulatory approval or
become commercially successful products. Other risks and uncertainties
include those identified under the heading “Risk Factors” in the
Company’s Annual Report on Form 10-K for the year ended
Source:
Verastem, Inc.
Brian Sullivan, 617-252-9314
bsullivan@verastem.com
