Date: 2015-01-16
Type of information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of results in in Cancer Research
Company: Verastem (USA - CA)
Product: VS-5584
Action
mechanism: 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. In preclinical studies, VS-5584 has been shown to reduce the percentage of cancer stem cells and induce tumor regression in chemotherapy-resistant models. Verastem is currently conducting a Phase 1 dose escalation trial of VS-5584 in patients with advanced solid tumors
Disease:
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On January 16, 2015, Verastem, focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, announced that a paper, titled “PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells,” has been published in Cancer Research, a peer-reviewed journal of the American Association for Cancer Research (AACR). The paper discusses results from preclinical research evaluating VS-5584, a highly potent, selective small molecule inhibitor of mTORC1/2 and Class I PI3K kinases, which preferentially targets cancer stem cells (CSCs) in vitro and in vivo. CSCs represent a subpopulation of cancer cells that have tumor-initiating capability, are particularly resistant to chemotherapy and can mediate tumor recurrence both locally and at metastatic sites.
The study results demonstrated that VS-5584 is up to 30-fold more potent in inhibiting the proliferation and survival of CSCs compared to non-CSCs in solid tumor cell populations. VS-5584 preferentially diminished CSC levels in multiple mouse xenograft models of human cancer. Similarly, VS-5584 treatment ex vivo preferentially reduced CSCs in surgically resected breast and ovarian patient tumors. In contrast, chemotherapeutics such as paclitaxel, cisplatin and etoposide effectively targeted bulk tumor cells, but enriched CSCs. Mechanistic investigations revealed that 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. Consistent with CSC ablation, VS-5584 delayed tumor regrowth following chemotherapy in xenograft models of small cell lung cancer. These data help to elucidate the mechanism of VS-5584 targeting 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.
