Cancer stem cells are an underlying cause of a tumor’s ability to recur and metastasize even after initial treatment. Therefore, targeting those cancer stem cells could prove to be a valuable tool in the treatment of several different tumor types.
This is the pursuit of Cambridge, Massachusetts–based Verastem, a clinical-stage biopharmaceutical company that has concentrated its efforts on developing drugs that target cancer stem cells. In particular, Verastem is developing small-molecule inhibitors that target several pathways associated with the progression of cancer, including focal adhesion kinase (FAK), PI3K/mTOR, and Wnt.
While other approved or investigational small-molecule inhibitors target those pathways and are capable of killing the majority of tumor cells, long-term, durable responses are difficult to achieve with these drugs, as patients often develop a resistance to these therapies over time. Verastem is exploring the theory that a small minority of cancer stem cells are responsible for this acquired resistance, since these cells are often resistant to existing targeted therapies, chemotherapy, and radiation therapy. According to the company, 80% of all cancers have cancer stem cells that are implicated in epithelial solid tumors.
Verastem’s lead candidate is defactinib (VS-6063), which inhibits FAK, a protein that is expressed more in tumor tissue over normal tissue and particularly in cancers that are capable of becoming invasive or metastatic. Currently, the drug is being investigated in clinical studies for the treatment of mesothelioma and ovarian cancer, with plans to eventually investigate efficacy in breast cancer and lung cancer.
A phase II, double-blind, placebo-controlled trial to compare the efficacy of defactinib with a placebo in patients with malignant pleural mesothelioma is expected to begin enrolling patients this year. The study is enrolling patients who have not progressed following at least four cycles of treatment with pemetrexed/cisplatin or pemetrexed/ carboplatin. The drug has already received orphan drug designation from the FDA for mesothelioma.
A phase I/Ib, open-label, multicenter, dose-escalation trial of paclitaxel in combination with defactinib in patients with advanced ovarian cancer is currently enrolling patients. The study is designed to assess the pharmacokinetics and the anticancer activity of defactinib as well as determine what the proper dose of the drug should be in an eventual phase II study. The company has announced that one patient has achieved a complete response with the combination.
Verastem has several other compounds in development. An additional FAK inhibitor that is structurally distinct from defactinib, called VS-4718, is currently under investigation, and a phase I trial is enrolling patients to determine its efficacy in metastatic, nonhematologic malignancies.
Another compound being developed by Verastem is VS- 5584, a potent and selective small-molecule inhibitor of PI3K, mTORC1, and mTORC2. The company is planning to explore its use in solid tumors as well as lymphomas.
Additionally, Verastem is collaborating with Eisai to develop novel inhibitors of the Wnt pathway, which has been established as a key regulator of cancer stem cell development and survival.