Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations in tumor suppressor genes Neurofibromatosis 2 (NF2) and p16/ARF. Inactivation of NF2 results in the absence of its protein product, merlin. Merlin loss is a critical driver of mesothelioma tumorigenesis and correlates with FAK inhibitor sensitivity in preclinical models. p16 and ARF are tumor suppressors, which bind to and regulate proteins involved in cell cycle progression and apoptosis. NF2 and p16/ARF are frequently co-inactivated in mesothelioma. The study results demonstrated in vivo that inactivation of NF2 and p16/ARF cooperate to drive the development of highly aggressive mesothelioma characterized by enhanced disease progression and an increase in cancer stem cells.
Verastem's lead compound is VS-6063, an orally available agent that targets cancer stem cells through potent inhibition of focal adhesion kinase (FAK), a critical signaling pathway in the development and survival of cancer stem cells. Cancer stem cells are an underlying cause of tumor resistance to chemotherapy, recurrence, and ultimate disease progression.
"These findings provide strong genetic evidence for the cooperativity between merlin and p16/ARF loss of function in driving the development of highly aggressive malignant mesothelioma marked by an enhanced presence of cancer stem cells that drive tumor progression. Collectively, these data further support the concept that cancer stem cells play a key role in the aggressiveness of merlin-low mesothelioma." said Jonathan Pachter, Ph.D.
"The ongoing COMMAND trial is designed to evaluate the effect of VS-6063 in patients with mesothelioma. This study contributes to our understanding of the driving factors in mesothelioma aggressiveness. Merlin-low mesothelioma cells and tumors appear to be particularly sensitive to FAK inhibition, so we have designed COMMAND to evaluate the effect of FAK inhibition on both the overall mesothelioma patient population and also in those whose tumors are merlin-low. Through this approach we believe that we can determine the potential of VS-6063 for the treatment of patients with this highly aggressive form of cancer." said Dr. Joanna Horobin, Verastem Chief Medical Officer.
Verastem is currently conducting multiple trials of two FAK inhibitors: VS-6063 and VS-4718. VS-6063 is in the registration-directed COMMAND study for patients with mesothelioma, a Phase 2 study in NSCLC, a Phase 1/1b combination study of VS-6063 and weekly paclitaxel for patients with ovarian cancer and a Phase 1 trial in Japanese patients. VS-4718 is in a Phase 1 study for patients with advanced cancers. The Company is also developing VS-5584, a PI3K/mTOR inhibitor which is currently being studied in a Phase 1 trial in patients with advanced solid tumors or lymphoma.
The Cancer Research abstract can be accessed at http://bit.ly/1bnjwiS.
About Malignant Pleural Mesothelioma
Malignant pleural mesothelioma is an aggressive form of cancer that occurs in the mesothelium, the thin layer of tissue that covers the lungs. Mesothelioma is associated with exposure to asbestos in most cases. According to the World Health Organization, a total of 59,000 deaths occur worldwide each year due to mesothelioma. Most mesotheliomas begin as one or more nodules that progressively grow to form a solid coating of tumor surrounding the lung leading to eventual suffocation and death. A high percentage of mesotheliomas contain cancer stem cells that are generally resistant to the currently available treatment options for advanced mesothelioma.
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 Robert Weinberg, Ph.D., scientific cofounder and chair of Verastem's Scientific Advisory Board, and Verastem has demonstrated that the FAK pathway is critical for the growth and survival of cancer stem cells. VS-6063 is currently being studied in the registration-directed COMMAND trial in mesothelioma (www.COMMANDmeso.com), a Phase 1/1b study in combination with paclitaxel for patients with ovarian cancer, a Phase 1 study in Japan in patients with advanced solid tumors and a Phase 2 trial in patients with Kras-mutated non-small cell lung cancer. VS-6063 has been granted orphan drug designation in the U.S. and E.U. for use in mesothelioma.
VS-4718 is an orally available compound designed to target cancer stem cells through the potent inhibition of focal adhesion kinase (FAK). VS-4718 is currently being studied in a Phase 1 dose escalation study in patients with advanced cancers.
- Craig W. Menges, Yuwaraj Kadariya, Deborah Altomare, Jacqueline Talarchek1, Erin Neumann-Domer, Yue Wu1, Guang-Hui Xiao, Irina M. Shapiro, Vihren N. Kolev, Jonathan A. Pachter, Andres J. Klein-Szanto, and Joseph R. Testa1 (2014). Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53–miR-34a–c-Met Axis Cancer Research DOI: 10.1158/0008-5472.CAN-13-2062