Abstract
Abstract Cancer is a disease driven by the acquisition and clonal selection of gain- and loss-of-function genetic alterations. While a fuller understanding of the pattern, specificity and biological consequences of such genetic events remains for us to elucidate, it is now clear that therapeutics directed against the genetic underpinnings of cancer have had a marked clinical impact. The growing list of therapeutics with efficacy in defined genetic settings includes imatinib in BCR-ABL driven CML, trastuzumab in HER2+ breast cancer, and erlotinib and gefitinib in EGFR mutated lung cancer among others. Indeed, the efficacy of small molecule inhibitors of KIT, PDGFR, HER2, EGFR, BRAF and ALK in a diversity of malignances including GIST, lung cancer and melanoma support the notion that a new generation of efficacious drugs is emerging. Nonetheless, we can articulate 5 key road-blocks to the more rapid and widespread application of the “genetic paradigm” including 1) an incomplete understanding of the genetic alterations characteristic of human cancer; 2) the difficulty in developing therapeutics that reverse the activity of non-kinase oncogenes (e.g. RAS and MYC) or reverse the consequences of tumor suppressor mutations (e.g. p53, RB1); 3) the development of resistance to genetic targeted therapy; 4) the need to identify highly active novel combination therapy regimens and 5) the lack of a robust pre-clinical translational infrastructure allowing for the more accurate prediction of human clinical trial results. This lecture will discuss strategic approaches to these 5 problems in the context of novel emerging therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr PL01-01. doi:1538-7445.AM2012-PL01-01
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