|April 9, 2014|
|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
Title: VS-6063 (defactinib) targets cancer stem cells directly
and through inhibition of tumor-associated macrophages and cytokine
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.
Title: Focal adhesion kinase (FAK) inhibitor VS-6063 (defactinib)
preferentially targets cancer stem cells in triple negative breast cancer
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
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
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.
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
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.
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