The goal of this application is to investigate the unexpected role we have recently identified for anti-M?llerian hormone (AMH) in supporting the metastatic and drug resistance properties of aggressive lung cancer. Lung cancer kills approximately 160,000 people in the US annually, with a 5 year survival rate of ~16%. As a chaperone protein, heat shock protein 90 (HSP90) is essential to support the activity of many proteins involved in oncogenesis, and HSP90 overexpression in tumors correlates with worse outcomes. The clinically promising HSP90 inhibitor ganetespib is showing considerable promise in late stage clinical trials, including those for NSCLC, and has recently been granted Fast Track status for NSCLC. Our initial goal was to understand and further improve the activity of this and other HSP90 inhibitors. Following extensive screening of a targeted siRNA library, we identified AMH and its receptor AMHRII as significant regulators of resistance to ganetespib. AMH is a member of the transforming growth factor (TGF)-? ligand family, and AMHRII heterodimerizes with co-receptors also required by TGF-? and BMP, influencing common effector cascades. The role for TGF-? signaling in NSCLC proliferation, survival and metastasis is well established, but no prior study has ever identified a role for AMH and AMHRII in this context. Our preliminary data suggests a novel autocrine-signaling loop involving AMH and AMHIIR in multiple NSCLC cell lines, and also suggest a monoclonal antibody to AMHRII sensitizes cells to HSP90 inhibition. AMHRII stability was recently shown to be highly dependent on HSP90, while we have shown that there is significant expression of AMH and AMHRII in a subset of lung cancer cell lines as well as in many primary lung cancers. We hypothesize that previously undetected autocrine AMH signaling plays a critical role in supporting the TGF-? pathway in a subpopulation of lung cancers, that AMH/AMHRII inhibition may potentiate the efficacy of ganetespib and other therapies, and that AMH and AMHRII may be utilized as biomarkers for tumor aggressiveness. Our long-term goals are to better understand the role of AMH and AMHRII in therapeutic response to ganetespib and other agents, and use this information to improve the treatment of lung cancer patients. In this proposal, the first aim will use siRNA and overexpression experiments to probe the functional interactions of AMH with TGF-? signaling in lung cancer cells.
The second aim will explore the in vitro and in vivo effects of inhibiting AMH and AMHRII for drug response, and use tissue microarrays of human lung cancer to gauge expression of AMH, AMHRII, HSP90 and related partners as predictors of tumor stage, grade, and prognosis.

Public Health Relevance

Lung cancer kills approximately 160,000 people in the US annually. In contrast to many other forms of cancer, treatment options have not improved significantly in the past decades, with the 5 year survival rate remaining around 16%. Ganetespib, an agent targeting heat shock protein 90 (HSP90), has been showing considerable promise in extending the lives of patients with lung cancer. The entire goal of this project is to exploit promising preliminary data to improve the application of ganetespib in lung cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-C (M1))
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Arya, Suresh
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Research Institute of Fox Chase Cancer Center
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Beck, Tim N; Smith, Chad H; Flieder, Douglas B et al. (2017) Head and neck squamous cell carcinoma: Ambiguous human papillomavirus status, elevated p16, and deleted retinoblastoma 1. Head Neck 39:E34-E39
Zhang, Yong-Wei; Nasto, Rochelle E; Jablonski, Sandra A et al. (2017) RNA Interference Screening to Identify Proliferation Determinants in Breast Cancer Cells. Bio Protoc 7:
Beck, Tim N; Georgopoulos, Rachel; Shagisultanova, Elena I et al. (2016) EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer. Mol Cancer Ther 15:2486-2497
Gaponova, Anna V; Nikonova, Anna S; Deneka, Alexander et al. (2016) A Novel HSP90 Inhibitor-Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer. Clin Cancer Res 22:5120-5129
Beck, Tim N; Golemis, Erica A (2016) Genomic insights into head and neck cancer. Cancers Head Neck 1:
Kudinov, Alexander E; Deneka, Alexander; Nikonova, Anna S et al. (2016) Musashi-2 (MSI2) supports TGF-? signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis. Proc Natl Acad Sci U S A 113:6955-60
Beck, Tim N; Golemis, Erica A; Geynisman, Daniel M (2016) Reply to Francesco Piva, Matteo Santoni, Marina Scarpelli, et al's Letter to the Editor re: Daniel M. Geynisman. Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic and Rapid Response in Papillary Renal Cell Carcinoma with S Eur Urol 70:e75-6
Beck, Tim N; Korobeynikov, Vladislav A; Kudinov, Alexander E et al. (2016) Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer. Cell Rep 16:657-71
Zhang, Y-W; Nasto, R E; Varghese, R et al. (2016) Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation. Oncogene 35:1643-56
Shagisultanova, Elena; Gaponova, Anna V; Gabbasov, Rashid et al. (2015) Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases. Gene 567:1-11

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