Abstract IA11: Functionalization the cancer genome

Abstract As we begin to implement next-generation sequencing into patient care, a central challenge will involve determining which aberrations in a given tumor represent “drivers” that determine tumor behavior versus “passengers” resultant from the inherent instability of cancer genomes. Critically even within cancer genes, many aberrations could still be passengers. Indeed, given the broad landscape of aberrations in human tumors, it is possible that genomic aberrations in a cancer gene could be hypomorphs (decreasing activity of a tumor suppressor gene), hypermorphs (increasing activity of an oncogene) or neomorphs (changing function of the protein). Neomorphs such as those engendered by mutations in IDH1 in glioma could be particularly challenging as their therapeutics liabilities are not likely to be predictable from known functions of the wild-type protein. Targeting driver aberrations should improve outcomes for patients, while targeting passenger aberrations would be without benefit and may instead result in unnecessary toxicity and delay implementation of effective therapies. It will also be critical to select the drug or drugs most likely to benefit each patient based on underlying aberrations in their own tumor. Unfortunately, there is a complete lack of practical high-throughput platforms able to identify and select optimal therapies targeting driver aberrations. We have implemented a high-throughput pipeline that consists of generation of patient tumor mutations in open reading frames (ORF) and determining the effect of shRNA, wild-type ORFs and mutant ORFs in the BAF3 IL3 dependent sensor line. Aberrations that increase cell viability and proliferation are established as stable lines. Stable lines are then probed with a chemical genomic library of tool compounds targeting critical pathways as well as through a high-throughput reverse phase protein array (RPPA) functional proteomics platform. The intersection of functional effects in the platforms identifies potential drivers and elicits their mechanistic activity and potential therapeutic liabilities. This pipeline has the potential to elicit tumor drivers and identify individualized therapeutic approaches. Citation Format: Gordon B. Mills, Yiling Lu, Wai Ting Cheung, Kenneth Scott, Han Liang. Functionalization the cancer genome [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA11.