Abstract 1138: Rapid validation of a novel kinase target using a large scale genomic database and matched patient derived tumor models.

Abstract

Abstract Target discovery and validation in oncology has largely relied on molecular and functional studies performed in cell lines. Recent advances in genomics have now afforded large databases based on well-characterized tumor tissue, which has enabled direct investigation of patient tumors for novel targets. Following these discoveries, it is routine to perform functional studies in cell line-based systems; however, it is often difficult to find relevant cell line model and if identified, they can be confounded with artifacts created from decades of culture. The result can be a target validation process which takes considerable time and does not readily translate to clinical relevance. We report here the creation and use of a target validation platform based on a large-scale genomic database matched to patient-derived tumor models. The platform relies on Molecular Response's proprietary bank of more than 144,000 patient derived tumors, of which nearly 400 tumors have been genomically characterized and databased for target discovery studies. The database is growing, but currently features the following cancer indications: colon carcinoma, NSCLC, melanoma, ovarian carcinoma, prostate and non-hodgkins lymphoma. Upon discovery of a novel target, tumors of interest are immediately implanted into mice to perform functional studies in direct patient derived models–either in vivo or using mouse-passaged cells for broader ex vivo studies. Through use of this platform, we have identified a novel kinase target for potential therapeutic development. We investigated prevalence of target overexpression across 7 cancer indications, and identified melanoma as a clinical indication of high interest. We examined growth characteristics from patient tumors featuring high kinase gene expression vs. low expression to help characterize the role of this target in oncology disease progression. Finally, we performed functional knockdown studies in patient derived models to further validate this novel kinase as a druggable target of pharmaceutical interest. Studies are ongoing to develop small molecule and antibody-based therapeutics that will serve as drug candidates for further development. Citation Format: Thomas Broudy, Sandeep Sanga, Jill Ricono, Mohit Trikha, Cyrus Mirsaidi, Kesavan Nair Praveen. Rapid validation of a novel kinase target using a large scale genomic database and matched patient derived tumor models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1138. doi:10.1158/1538-7445.AM2013-1138