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Y. Wang
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.07 - Targeting Cancer Stem Cells in Small Cell Lung Cancer (ID 2727)
17:20 - 17:25 | Author(s): Y. Wang
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) is an extremely aggressive cancer with limited treatment options and poor outcome. The majority of SCLC patients respond to frontline chemotherapy, but experience rapid recurrence with metastasis, that may be attributed to the prevalence of cancer stem cells (CSCs). We previously demonstrated that PI3K/mTOR signaling is key for CSCs in cell culture and solid tumor models. As shown with a dual PI3K/mTOR inhibitor, VS-5584, inhibition of multiple PI3K isoforms and mTOR is necessary to achieve preferential targeting of CSCs.
Methods:
Antitumor activity of VS-5584 was assessed by in vitro proliferation assay as well as in multiple xenograft models in vivo, including patient-derived xenograft models. Anti-CSC activity was measured by the side-population CSC assay in vitro and in limiting dilution tumor initiation assay in vivo.
Results:
VS-5584 inhibited SCLC growth in vitro at sub-µM IC50, and was synergistic with cisplatin and etoposide in reducing the viability of SCLC cells. In vivo, single agent VS-5584 (20 mg/kg, 3 days per week dosing, MWF) demonstrated robust anti-CSC activity in the NCI-H841 SCLC model by reducing tumor initiating potential 70-fold (p=5x10[-6]). In tandem, VS-5584 partially reduced tumor growth of the NCI-H841 xenograft tumors. Furthermore, a VS-5584 dose dependency was evident, both for tumor initiating potential and tumor growth reduction. When VS-5584 was combined with cisplatin and etoposide, the standard of care agents for SCLC, an increased tumor growth inhibition was observed whether VS-5584 was concurrently administered or added sequentially following the dual chemotherapy. In the SCLC PDX model, combination treatment also suppressed the regrowth of the tumor following cessation of chemotherapy for extended duration. VS-5584 was found to preferentially induce apoptosis in CSCs in multiple cell lines, indicating that these cells are eliminated through cell death-related mechanism. Importantly, we demonstrated that for eradication of CSCs it is necessary to inhibit simultaneously multiple PI3K isoforms and mTOR pathways.
Conclusion:
The VS-5584 pre-clinical findings support the preferential targeting of CSCs in SCLC models and provide an important rationale for advancing clinical development of the compound. A phase 1 dose finding clinical trial is on-going to establish a Phase 2 dose of VS-5584 and explore target inhibition. VS-5584 alone or in combination with standard of care chemotherapy may lengthen the time to relapse and improve outcome for patients with small cell lung cancer.
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.05 - The Cancer Stem Cell Inhibitors VS-6063 and VS-5584 Exhibit Synergistic Anticancer Activity in Pre-Clinical Models of Mesothelioma (ID 2753)
17:28 - 17:39 | Author(s): Y. Wang
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum usually resulting from prior exposure to asbestos. Median overall survival with standard of care (SOC) chemotherapy is only 12 months from diagnosis. This poor prognosis may be attributable at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. VS-6063 (defactinib) is an oral small molecule that targets cancer stem cells through the inhibition of focal adhesion kinase (FAK). VS-6063 has demonstrated tolerability, target inhibition, and preliminary signs of clinical activity as a single agent and in combination with paclitaxel in Phase 1 clinical trials (Jones et al., J Clin Oncol 29: 2011 (suppl; abstr 3002); Patel et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 5521)). Currently, VS-6063 is being tested in a randomized, double-blind, placebo-controlled trial in malignant pleural mesothelioma immediately following front-line therapy (COMMAND Trial, NCT01870609). In an effort to identify additional mesothelioma patients who may benefit from a CSC targeting agent, we sought to identify compounds that show synergistic anticancer activity with VS-6063. PI3K/mTOR inhibitors were previously demonstrated to show activity in mesothelioma. VS-5584 is a potent oral small molecule that selectively kills CSCs by targeting multiple PI3K isoforms and mTORC1/2 (Kolev et al, Cancer Res; 75:1, 2014). VS-5584 is currently being investigated as a single agent in a Phase 1 clinical trial, (NCT01991938).
Methods:
The synergy between VS-6063 and VS-5584 was demonstrated in vitro using cell viability assays analyzed by CalcuSyn, HSA and Loewe models. CSCs from mesothelioma cell lines were assessed by the Aldefluor+ flow cytometric assays. The anti-tumor activity of the VS-6063 and VS-5584 combination treatment was tested with in vivo mouse mesothelioma xenograft models.
Results:
A dual PI3K/mTOR inhibitor VS-5584 showed synergistic activity with a FAK inhibitor, VS-6063. VS-5584 further enhanced reduction of mesothelioma CSCs by VS-6063 measured by the Aldefluor+ assay in Mero-14 mesothelioma cells. In a 3D matrigel cell viability assay, the combination of VS-6063 and VS-5584 displayed synergistic reduction in cell viability based on multiple combination analysis models. In a MM87 mesothelioma xenograft model in vivo, the single agent treatment with either VS-6063 or VS-5584 was active in inhibiting mesothelioma tumor growth. Combination treatment further enhanced the antitumor efficacy of either agent alone (p <0.0001).
Conclusion:
VS-6063 (defactinib) and VS-5584 exhibit synergistic anticancer activity in preclinical models of mesothelioma. These data provide a strong preclinical rationale for the open dose-escalation Phase I clinical trial of VS-6063 and VS-5584 in patients with relapsed mesothelioma (NCT02372227).
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