Pre-clinical identification of therapeutic targets in Type 1 Papillary Renal Cell Carcinoma

Authors

• R Pahwa
• A Giri
• J Dubhashi
• C Sourbier
• T Craig
• WM Linehan
• L Neckers
• R Srinivasan

Abstract

Papillary renal cell carcinoma is the second most common form of kidney cancer, accounting for 15 to 20% of all cases, and occurs in both sporadic and inherited forms. Two histologic subtypes of papillary RCC, types 1 and 2, have been described with additional subtypes discernible by molecular profiling. Despite advances in the management of other forms of kidney cancer, there are currently no accepted standard treatment options for patients with advanced papillary RCC. Activating gene mutations of MET are identified in the germline of hereditary papillary renal cell carcinoma patients and somatic MET mutations are found in a subset of patients with non-inherited, sporadic papillary renal carcinoma. While MET kinase inhibitors are active in some of these patients, primary and acquired resistance is common, prompting us to investigate possible therapeutic alternatives. In collaborations with NCATS, an unbiased quantitative high throughput screening(qHTS) of about 1900 clinically relevant small molecule inhibitors was performed using patient derived papillary RCC cell lines generated in our laboratory. Based on this screen, two classes of drugs-Hsp90 inhibitors and Src family inhibitors were identified as molecules of interest with potent antitumor activity. Based on these data, we sought to explore the effect of Hsp90 and Src inhibitors on papillary RCC tumors. The Hsp90 inhibitor, SNX2112 and the multikinase Src inhibitor, Dasatinib exerted potent anti-tumor activity in vitro as single agents. Additionally, potent synergy was noted when these agents were combined. Since both agents can alter the intracellular levels and/or activity of a broad range of oncologically relevant targets, we sought to identify specific targets/pathways of relevance in papillary RCC. Selective knockdown experiments as well as selective pharmacologic inhibition of specific targets suggest that effects of these agents on BIRC5, Cyclin D, cMYC, VEGF and the MAPK/ERK, and PI3K/AKT pathways may mediate their anti-tumor activity. In vivo studies to further evaluate the activity of both classes of agents are ongoing. These data provide the foundation for further pre-clinical and clinical evaluation of Hsp90 and Src-family inhibitors in type 1 papillary RCC.

Scientific Focus Area: Cancer Biology

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