Research

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Verastem ResourcesTargeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
July 04, 2016
Nature Medicine 22, 851–860 (2016)

Hong Jiang1,2, Samarth Hegde1,2, Brett L Knolhoff1,2, Yu Zhu1,2, John M Herndon1,2, Melissa A Meyer1,2 Timothy M Nywening3, William G Hawkins3,4, Irina M Shapiro5, David T Weaver5, Jonathan A Pachter5, Andrea Wang-Gillam1,4 & David G DeNardo1,24,6

Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8+ cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-KrasG12D;Trp53flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. 2Integrating Communications within the Cancer Environment (ICCE) Institute, Washington University School of Medicine, St. Louis, Missouri, USA. 3Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. 4Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA. 5Verastem Inc., Needham, Massachusetts, USA. 6Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. Correspondence should be addressed to D.G.D. (ddenardo@dom.wustl.edu).

Received 5 March; accepted 10 May; published online 4 July 2016; doi:10.1038/nm.4123

Verastem ResourcesNuclear FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor Immunity
September 24, 2015
Cell 163, 160–173

Alan Serrels,1,7,* Tom Lund,1,7 Bryan Serrels,1 Adam Byron,1 Rhoanne C. McPherson,2 Alexander von Kriegsheim,1 Laura Go´ mez-Cuadrado,1 Marta Canel,1 Morwenna Muir,1 Jennifer E. Ring,3 Eleni Maniati,4 Andrew H. Sims,1 Jonathan A. Pachter,3 Valerie G. Brunton,1 Nick Gilbert,5 Stephen M. Anderton,2 Robert J.B. Nibbs,6 and Margaret C. Frame,1,*

Abstract
Focal adhesion kinase (FAK) promotes anti-tumor immune evasion. Specifically, the kinase activity of nuclear-targeted FAK in squamous cell carcinoma (SCC) cells drives exhaustion of CD8+ T cells and recruitment of regulatory T cells (Tregs) in the tumor microenvironment by regulating chemokine/cytokine and ligand-receptor networks, including via transcription of Ccl5, which is crucial. These changes inhibit antigen-primed cytotoxic CD8+ T cell activity, permitting growth of FAK-expressing tumors. Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Furthermore, FAK’s immuno-modulatory nuclear activities may be specific to cancerous squamous epithelial cells, as normal keratinocytes do not have nuclear FAK. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8+ T cell-mediated anti-tumor response. Therefore, FAK inhibitors may trigger immune-mediated tumor regression, providing previously unrecognized therapeutic opportunities.

1Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK 2MRC Centre for Inflammation Research, The Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK 3Verastem Inc., 117 Kendrick Street, Suite 500, Needham, MA 02494, USA 4Queen Mary, University of London, Centre for Cancer and Inflammation, Charterhouse Square, London EC1M 6BQ, UK 5MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK 6Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 7Co-first author *Correspondence: a.serrels@ed.ac.uk (A.S.), m.frame@ed.ac.uk (M.C.F.)

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