Research

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Verastem ResourcesPI3K/mTOR Dual Inhibitor VS-5584 Preferentially Targets Cancer Stem Cells
Vihren N. Kolev1, Quentin G.Wright1, Christian M.Vidal1, Jennifer E. Ring1, Irina M. Shapiro1, Jill Ricono2, David T.Weaver1, Mahesh V. Padval1, Jonathan A. Pachter1, and Qunli Xu1
January 15, 2015
American Association for Cancer Research

Abstract

Cancer stem cells (CSC) have been implicated in disease recurrence, metastasis, and therapeutic resistance, but effective targeting strategies for these cells are still wanting. VS-5584 is a potent and selective dual inhibitor of mTORC1/2 and class I PI 3-kinases. Here, we report that VS-5584 is up to 30-fold more potent in inhibiting the proliferation and survival of CSC compared with non-CSC in solid tumor cell populations. VS- 5584 preferentially diminished CSC levels in multiple mouse xenograft models of human cancer, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Likewise, VS-5584 treatment ex vivo preferentially reduced CSC in surgically resected breast and ovarian patient tumors. In contrast, chemotherapeutics such as paclitaxel and cisplatin were less effective in targeting CSC than bulk tumor cells. Mechanistic investigations revealed that preferential targeting of CSC required inhibition of multiple components of the PI3K–mTOR pathway: coordinate RNAi-mediated silencing of PI3Ka, PI3Kb, and mTOR phenocopied the effect of VS- 5584, exhibiting the strongest preferential targeting of CSC, while silencing of individual PI3K isoforms or mTOR failed to replicate the effect of VS-5584. Consistent with CSC ablation, VS-5584 delayed tumor regrowth following chemotherapy in xenograft models of small-cell lung cancer. Taken together, the preferential targeting of CSC prompts a new paradigm for clinical testing of VS-5584: clinical trials designed with CSCdirected endpoints may facilitate demonstration of the therapeutic benefit of VS-5584. We suggest that combining VS-5584 with classic chemotherapy that debulks tumors may engender a more effective strategy to achieve durable remissions in patients with cancer. Cancer Res; 75(2); 1–10. 2014 AACR.

1 Verastem Inc., Needham, Massachusetts. 2 Molecular Response, San Diego, California.

Verastem ResourcesMerlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship
Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, Wright Q, Weaver DT, Menges C, Padval M, McClatchey AI, Xu Q, Testa JR, Pachter JA.
May 21, 2014
Vol. 6, Issue 237, p. 237ra68 Science Transitional Medicine DOI: 10.1126/scitranslmed.3008639

Verastem ResourcesVS-5584, a Novel and Highly Selective PI3K/mTOR Kinase Inhibitor for the Treatment of Cancer
Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC, Ong LC, Cheong A, Ng BK, Amalini C, Madan B, Nagaraj H, Jayaraman R, Pasha KM, Ethirajulu K, Chng WJ, Mustafa N, Goh BC, Benes C, McDermott U, Garnett M, Dymock B, and Wood JW.
February 18, 2013
Molecular Cancer Therapeutics: Mol Cancer Ther; 12(2); 151–61. ©2012 AACR.

Verastem ResourcesThe outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions.
Shibue T, Brooks MW, Inan MF, Reinhardt F, Weinberg RA.
August 02, 2012
Cancer Discov. 2012 Aug;2(8):706-21

Verastem ResourcesStochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells
Piyush B. Gupta, Christine M. Fillmore, Guozhi Jiang, Sagi D. Shapira, Kai Tao, Charlotte Kuperwasser, Eric S. Lander
July 26, 2011
Cell, Volume 146, Issue 4, 633-644

Verastem ResourcesHallmarks of Cancer: The Next Generation
Douglas Hanahan, Robert A. Weinberg
March 04, 2011
Cell, Volume 144, Issue 5, 646-674

Verastem ResourcesCancer Stem Cells: Mirage or Reality?
Gupta PB, Chaffer CL, Weinberg RA.
September 15, 2009
Nat Med. 2009 Sep;15(9):1010-2.

Verastem ResourcesIdentification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES
August 13, 2009
Cell. 2009 Aug 21;138(4):645-59

Verastem ResourcesThe Epithelial-Mesenchymal Transition Generates Cells With Properties of Stem Cells.
Sendurai A. Mani, Wenjun Guo, Mai-Jing Liao, Elinor Ng. Eaton, Ayyakkannu Ayyanan, Alicia Y. Zhou, Mary Brooks, Ferenc Reinhard, Cheng Cheng Zhang, Michail Shipitsin, Lauren L. Campbell, Kornelia Polyak, Cathrin Brisken, Jing Yang, and Robert A. Weinberg.
May 08, 2008
Cell, Volume 133, Issue 4, 704-715