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V. Kolev
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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): V. Kolev
- 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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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.01 - FAK Inhibitor VS-6063 Targets Mesothelioma Cancer Stem Cells: Rationale for Maintenance Therapy after Conventional Chemotherapy (ID 2710)
18:30 - 18:35 | Author(s): V. Kolev
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum with median overall survival with standard of care (SOC) chemotherapy only 12 months from diagnosis. This poor prognosis may be attributed at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. Focal adhesion kinase (FAK) plays an essential role in the survival, self-renewal and tumor-initiating capability of CSCs. The FAK inhibitor VS-6063 (defactinib) is currently being tested in patients with MPM following disease control on standard pemetrexed/platinum chemotherapy (COMMAND, ClinicalTrials.gov NCT01870609).
Methods:
An Aldefluor assay, previously validated as a CSC assay (Shapiro et al., 2014), was used to assess the effects of chemotherapy or VS-6063 on CSCs in vitro. Tumor initiating potential of MPM cells after treatment with SOC agents, and VS-6063 alone or in combination with pemetrexed was measured in vivo. CSC marker expression in MPM patient tumor samples was measured by IHC, Q-PCR and RNASeq analysis. Novel CSC markers were validated in an in vivo limiting dilution assay.
Results:
Treatment of a human MPM cell line with pemetrexed or cisplatin, the SOC therapy for mesothelioma, resulted in a 6-fold enrichment of ALDH-positive CSCs. In direct contrast, the FAK inhibitor VS-6063 markedly reduced the proportion of CSCs. Control and pemetrexed-treated MPM cells showed robust tumor initiation in vivo, while cells treated with VS-6063 alone or VS-6063 plus pemetrexed had decreased tumor initiating capacity. FAK inhibitor was found to selectively induce apoptosis in CSCs, indicating that the mechanism of their elimination is cell death. In addition to ALDH, several new mesothelioma CSC markers were validated in in vivo limiting dilution assay and their clinical utility was assessed. An increase in CSC markers, including ALDH1, CD133 and CXCR2, was observed in tumor samples from 11 patients following first line pemetrexed-cisplatin chemotherapy. In tumor biopsies from MPM patients treated for 12 days with VS-6063, tumor pFAK (Y397) and expression of CSC markers was reduced. Interestingly, gene expression analysis of these samples revealed an inhibition of CSC pathways after VS-6063 administration. VS-6063 maintained the effect of chemotherapy in patient-derived xenograft (PDX) mouse model. Treatment with pemetrexed/cisplatin resulted in tumor growth inhibition followed by rapid tumor re-growth upon cessation of the treatment. Tumor re-growth was substantially delayed when FAK inhibitor was administered after chemotherapy.
Conclusion:
These data provide a strong rationale for the current clinical testing of VS-6063 following treatment with pemetrexed plus platinum to potentially prolong time to progression in patients with mesothelioma.
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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): V. Kolev
- 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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