On July 5, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the publication of preclinical research in the journal Nature Medicine by the Company’s researchers and scientific collaborators (Press release, Verastem, JUL 5, 2016, View Source;p=RssLanding&cat=news&id=2181887 [SID:1234513711]). The research, which was led by David G. DeNardo, PhD, Assistant Professor of Medicine, Division of Oncology, Department of Immunology, Washington University School of Medicine in St. Louis, and co-author of the paper, demonstrated that focal adhesion kinase (FAK) inhibition decreases fibrosis and immunosuppressive cell populations in pancreatic ductal adenocarcinoma (PDAC), rendering previously unresponsive tumors sensitive to chemo- and immunotherapy.
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"The application of immunotherapy holds great promise to improve outcomes for patients with pancreatic cancer, as it has for melanoma and lung cancer patients," said Dr. DeNardo. "To date, however, attempts at immunotherapy in PDAC have achieved limited clinical benefit when deployed as single agents. This is likely due in part to the presence of a uniquely immunosuppressive tumor microenvironment which is dominant in most human cases of PDAC. Major drivers of this pro-tumorigenic microenvironment include a highly fibrotic stroma and extensive infiltration by immunosuppressive cell populations. Thus, agents that can potentially overcome excessive fibrosis while altering immune suppression would be particularly attractive targets for PDAC."
The paper, titled "Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy," (Jiang, et al., advanced online publication, July 4, 2016 (doi:10.1038/nm.4123) describes the therapeutic targeting of FAK in in vivo murine PDAC models. Prior research has demonstrated that hyperactivated FAK activity is a significant regulator of the fibrotic and immunosuppressive tumor microenvironment (TME) in PDAC tumor cells.
In this study, researchers show that FAK signaling is a key driver of fibrosis, immunosuppression and PDAC progression. It was then demonstrated that single-agent treatment with Verastem’s FAK inhibitor VS-4718 significantly limited tumor progression, resulting in a doubling of survival in an in vivo model of human PDAC. This slowing of tumor progression was associated with dramatically reduced tumor fibrosis, and a reduced number of tumor-infiltrating immunosuppressive cells. Given these findings, it was then hypothesized that the resulting effects of FAK inhibition on the TME may render PDAC tumors more sensitive to immunotherapy. Study results then demonstrated that FAK inhibition rendered previously unresponsive in vivo models responsive to T cell therapy and anti-PD1 antagonists. These data strongly support the ongoing clinical evaluation of FAK inhibitors in combination with checkpoint immunotherapy in patients with pancreatic cancer.
"FAK signaling has been shown to be important in several carcinomas, including pancreatic tumors, but its compelling role in creating an immunosuppressive tumor microenvironment is just emerging," said Jonathan Pachter, PhD, Chief Scientific Officer of Verastem, and co-author of the paper. "Another study, recently published in Cell, found that FAK inhibition can modulate certain immune cell populations, namely CD8+ T cells and Tregs, enabling an immune response that destroys tumors. Similarly, in the current study, we found that FAK inhibition alters tumor cell production of pro-inflammatory and immunosuppressive cytokines and reduces the tumor’s ability to avoid immune surveillance. Together these findings provide important support and rationale for the ongoing Phase 1 dose-escalation clinical study evaluating Verastem’s FAK inhibitor VS-6063 in combination with pembrolizumab and gemcitabine in patients with pancreatic cancer."
In early 2016, Verastem launched a new clinical development program focused on advancing its FAK inhibitors in combination with immuno-oncology agents and other current and emerging standard of care treatments. The Company’s lead FAK inhibitor, VS-6063 is currently being evaluated in a Phase 1 dose-escalation study at the Washington University in Saint Louis in combination with Merck & Co.’s PD-1 inhibitor pembrolizumab and gemcitabine in patients with pancreatic cancer. VS-6063 is also the subject of an additional clinical collaboration between Merck KGaA, Pfizer and Verastem where it will be evaluated in a Phase 1/1b study in combination with avelumab, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, in patients with advanced ovarian cancer. This collaboration trial is expected to begin during the second half of 2016.
About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase encoded by the PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability. VS-6063 (defactinib) and VS-4718 are orally available compounds that are potent inhibitors of FAK. VS-6063 and VS-4718 utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. VS-6063 and VS-4718 are currently being studied in multiple clinical trials for patients with cancer.