Abstract IA08: Functionalizing the cancer genome
Authors: Mills Gordon B. 
Published: October 2015

Each individual and each individual cancer have unique combinations of genetic aberrations. This may explain why current therapies are effective for only a subset of patients. Matching the right treatment agent with the genetic profile of each patient's cancer—to make treatment more targeted, more effective and less toxic—is the central objective and the promise of implementation of personalized cancer therapy. Over the last few years, we have made significant progress in developing new technologies and approaches to determine the genetic makeup of an individual and of their own cancer. Combining this newfound ability to characterize the patient's tumor and their own genetic makeup with a toolkit of nearly 1,000 targeted experimental drugs and agents, designed to correct the consequences of the genomic aberrations in the cancer, is resulting in a “perfect storm” whereby we have the opportunity to have a major impact on patient outcomes. Our goal is to identify which drugs are most likely to benefit each individual patient by being the most effective and least toxic, thereby improving outcomes for cancer patients.

Comprehensive high-throughput sequencing analysis of human tumors in efforts such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) are providing a “parts” list of the aberrations present across cancer. 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. 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. It is thus necessary to develop practical high-throughput platforms able to identify and select optimal therapies for specific driver aberrations. The majority of efforts have focused on “cancer genes” rather than on specific aberrations in each cancer gene. Emerging evidence argues that different cancer mutations in cancer genes may engender different therapeutic liabilities.

Using a scalable high throughput platform able to analyze hundreds of mutations a month, we demonstrate that many mutations in cancer patients are indeed drivers. However, surprisingly, different mutations in a single cancer gene can result in markedly different therapeutic liabilities. Indeed, the most striking observation is that a number of the aberrations in cancer genes function as neomorphs with the aberration present in patient tumors activating unexpected pathways. This must be considered in linking mutational testing in patients to changes in patient management.

Citation Format: Gordon B. Mills. Functionalizing the cancer genome. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA08.