Preclinical Data Supportive of Ongoing Clinical
Collaboration Trials Evaluating FAK Inhibition in Combination with
Chemotherapeutic and Immunotherapeutic Agents
Verastem, Inc. (NASDAQ:VSTM), focused on discovering and
developing drugs to improve the survival and quality of life of
cancer patients, today announced scientific findings from studies
evaluating focal adhesion kinase (FAK) inhibition in preclinical
models of pancreatic and breast cancer with the publication of two
papers in the peer-reviewed journals, PLoS One and Oncotarget. The
two published articles continue to validate the underlying thesis
for ongoing clinical collaborations evaluating Verastem’s lead FAK
inhibitor defactinib in combination with chemotherapeutic and
leading immunotherapeutic agents in several difficult to treat
types of cancer.
Jonathan Pachter, Ph.D., Chief Scientific Officer of Verastem,
stated, “The data published in PLoS One illustrate the impact of
combining a FAK inhibitor with standard chemotherapy, demonstrating
inhibited tumor growth, along with limited metastatic dissemination
in pancreatic ductal adenocarcinoma (PDAC), one of the deadliest
types of cancer. Importantly, these data also provide additional
rationale for the ongoing clinical studies evaluating defactinib in
combination with Merck’s pembrolizumab for the treatment of
patients with pancreatic cancer. Our data in the Oncotarget paper
further delineate the anti-tumor mechanisms of our FAK inhibitors,
and demonstrate the benefit of adding a FAK inhibitor to overcome
key restrictive features of the tumor microenvironment (TME) to
enable longer survival and reduced metastatic outgrowth.”
PLoS ONE Publication Highlights Potential Role of FAK
Inhibition in Pancreatic Cancer
In a paper titled “The Extracellular Matrix and Focal Adhesion
Kinase Signaling Regulate Cancer Stem Cell Function in Pancreatic
Ductal Adenocarcinoma,” Verastem researchers, along with scientific
collaborators led by William Matsui at Johns Hopkins University
School of Medicine, describe findings demonstrating that FAK
inhibition extended the anti-tumor response to gemcitabine and
nab-paclitaxel (Gem-Pac) in preclinical models of PDAC. Prior
research has demonstrated that the desmoplastic TME of PDAC plays a
role in therapeutic resistance, and this study demonstrates that
intra-tumoral fibrosis enhances tumor-initiating and self-renewal
potential.
The researchers show that the TME in PDAC is dramatically
altered by several ECM proteins, including type I collagen. Type I
collagen increases PDAC tumor-initiating potential, self-renewal
and the frequency of cancer stem cells (CSCs) through the
activation of FAK. While FAK overexpression increased tumor
initiation, it was demonstrated that FAK inhibition reduced PDAC
growth in vitro and in vivo. In an in vivo murine PDAC model, FAK
inhibitor-treated tumors grew significantly slower than tumors in
vehicle-treated control animals. In addition, tumor regression was
enhanced by the addition of a FAK inhibitor to Gem-Pac and tumor
regrowth was also significantly delayed in animals treated with the
combination of a FAK inhibitor with Gem-Pac, as compared to Gem-Pac
alone.
Oncotarget Publication Describing the Preferential
Targeting of Cancer Stem Cells by FAK Inhibition in Breast Cancer
Models
In a paper by Vihren Kolev et al., titled “Inhibition of FAK
Kinase Activity Preferentially Targets Cancer Stem Cells,” Verastem
researchers demonstrated that FAK inhibition significantly reduced
the proportion of CSCs in mice bearing xenograft models of
triple-negative breast cancer (TNBC), as evidenced by a reduced
tumor-initiating capability upon re-implantation. In contrast, the
cytotoxic chemotherapeutic agents, paclitaxel and carboplatin,
enriched the number of CSCs. Importantly, FAK inhibition weakened
the chemotherapy-induced enrichment of CSCs in vitro and delayed
tumor regrowth following cessation of chemotherapy. In addition, an
active mutant form of β-catenin reversed the preferential targeting
of CSCs by FAK inhibition, suggesting that this targeting is
mediated, at least in part, through attenuating β-catenin
activation. The preferential targeting of CSCs by FAK inhibitors
provides a rationale for the clinical development of FAK inhibitors
aimed to increase durable responses for cancer patients.
About the Tumor Microenvironment
The TME encompasses multiple tumor and non-tumor cell
populations and an extracellular matrix that support cancer cell
survival. This includes immunosuppressive regulatory T-cells,
myeloid-derived suppressor cells, tumor-associated macrophages,
cancer-associated fibroblasts, and extracellular matrix proteins
that can hamper the entry and therapeutic benefit of cytotoxic
T-cells and anti-cancer drugs. In addition to targeting the
proliferative and survival signaling of cancer cells, Verastem’s
product candidates, including duvelisib and defactinib, also target
the TME to potentially improve response to therapy.
About Focal Adhesion Kinase and Defactinib
Defactinib (VS-6063) is an investigational inhibitor of Focal
Adhesion Kinase (FAK), a non-receptor tyrosine kinase encoded by
the PTK-2 gene that mediates oncogenic signaling in response to
cellular adhesion and growth factors.1 Based on the multi-faceted
roles of FAK, defactinib is used to treat cancer through modulation
of the tumor microenvironment, enhancement of anti-tumor immunity,
and reduction of cancer stem cells.2,3 Defactinib is currently
being evaluated in three separate clinical collaborations in
combination with immunotherapeutic agents for the treatment of
several different cancer types including pancreatic, ovarian,
non-small cell lung cancer, and mesothelioma. These studies are
combination clinical trials with pembrolizumab and avelumab from
Merck & Co. and Pfizer/Merck KGaA, respectively.4,5,6
Information about these and additional clinical trials evaluating
the safety and efficacy of defactinib can be found on
www.clinicaltrials.gov.
About Verastem, Inc.
Verastem, Inc. (NASDAQ:VSTM) is a biopharmaceutical company
focused on discovering and developing drugs to improve outcomes for
patients with cancer. Verastem is currently developing duvelisib, a
dual inhibitor of PI3K-delta and PI3K-gamma, which has successfully
met its primary endpoint in a Phase 2 study in iNHL and is
currently being evaluated in a Phase 3 clinical trial in patients
with CLL. In addition, Verastem is developing the FAK inhibitor
defactinib, which is currently being evaluated in three separate
clinical collaborations in combination with immunotherapeutic
agents for the treatment of several different cancer types,
including pancreatic cancer, ovarian cancer, non-small cell lung
cancer, and mesothelioma. Verastem’s product candidates seek to
treat cancer by modulating the local tumor microenvironment,
enhancing anti-tumor immunity, and reducing cancer stem cells. For
more information, please visit www.verastem.com.
Verastem, Inc. forward-looking statements notice:
This press release includes forward-looking statements about
Verastem’s strategy, future plans and prospects, including
statements regarding results of the Phase 2 DYNAMO® study, and
Verastem’s PI3K/mTOR and FAK programs generally, the structure of
our planned and pending clinical trials and the timeline and
indications for clinical development, including reporting top-line
data, and regulatory submissions and, our rights to develop or
commercialize our product candidates. The words “anticipate,”
“appear,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,”
“predict,” “project,” “target,” “potential,” “will,” “would,”
“could,” “should,” “continue,” and similar expressions are intended
to identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Each
forward-looking statement is subject to risks and uncertainties
that could cause actual results to differ materially from those
expressed or implied in such statement. Applicable risks and
uncertainties include the risks that the preclinical testing of
Verastem’s product candidates and preliminary or interim data from
clinical trials may not be predictive of the results or success of
ongoing or later clinical trials; that data may not be available
when expected, including for the Phase 3 DUO study; that enrollment
of clinical trials may take longer than expected; that our product
candidates will cause unexpected safety events or result in an
unmanageable safety profile as compared to their level of efficacy;
that duvelisib will be ineffective at treating patients with
lymphoid malignancies; that Verastem will be unable to successfully
initiate or complete the clinical development of its product
candidates; that the development of Verastem’s product candidates
will take longer or cost more than planned; that Verastem may not
have sufficient cash to fund its contemplated operations; that
Verastem or Infinity will fail to fully perform under the license
agreement; that the transition of the duvelisib program from
Infinity will not be completed; that Verastem will not pursue or
submit regulatory filings for its product candidates, including for
duvelisib in patients with CLL or iNHL; and that Verastem’s product
candidates will not receive regulatory approval, become
commercially successful products, or result in new treatment
options being offered to patients. Other risks and uncertainties
include those identified under the heading “Risk Factors” in
Verastem’s Annual Report on Form 10-K for the year ended December
31, 2015 as filed on March 3, 2016, the Company’s quarterly report
on Form 10-Q filed on November 7, 2016, and in any subsequent SEC
filings. The forward-looking statements contained in this press
release reflect Verastem’s current views with respect to future
events, and Verastem does not undertake and specifically disclaims
any obligation to update any forward-looking statements.
References
1 Schaller M.D. and Parsons J.T. Focal adhesion kinase: an
integrin-linked protein tyrosine kinase. Trends Cell Biol. 1993 3:
258-62.2 Jiang H et al. Targeting focal adhesion kinase renders
pancreatic cancers responsive to checkpoint immunotherapy. Nat Med
2016: Aug 22(8) 851-60.3 Sulzmaier F.J. et al. FAK in cancer:
mechanistic findings and clinical applications. Nature Rev Cancer.
2014 14: 598-610.4 www.clinicaltrials.gov, NCT025465315
www.clinicaltrials.gov, NCT029433176 www.clinicaltrials.gov,
NCT02758587
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version on businesswire.com: http://www.businesswire.com/news/home/20170725005355/en/
Verastem, Inc.Brian Sullivan, 781-292-4214Director,
Corporate Developmentbsullivan@verastem.com
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