Our ability to quickly and cost-effectively decode cancer genomes and identify somatic mutations has been revolutionized by deep sequencing technologies. In some instances, the identification of these somatic driver mutations has resulted in implementation of more effective therapeutic strategies for patients. However, in many instances knowledge of somatic drivers has not resulted in new therapeutic strategies. In some cases, these driver mutations are gain-of-function and targeted drugs have not yet been developed, such that further drug development will bridge the translational gap between genomic knowledge and clinical translation. However, in many cases the somatic driver mutations are not directly targetable because the mutations result in loss-of-function of the mutated gene. In these cases, we face a critical knowledge gap between understanding of the identity of molecular drivers of disease and understanding of the dysregulated signaling pathways that result from these loss-of-function genetic events. It will be important to close this knowledge gap in order to better understand the targeted therapies that can be effective for all somatic driver events, such that all cancer patients can receive effective, individually tailored therapies. My lab has developed ex vivo, functional screening platforms that can be applied directly to primary specimens from patients with hematologic malignancies. These assays are based on panels of drugs and can deliver information about the specific drugs (or combinations of drugs) to which a patient's tumor cells are hypersensitive. Integration of these functional data with genomic information about each patient's tumor cells has allowed us to accelerate the process by which we discover actionable therapeutic strategies that correlate with tumor genotypes. In addition, these assays are completed in a clinically relevant time frame of three days, such that the data from these assays can be used to directly inform therapeutic strategies, even in the absence of genomic information. In this lecture, I will provide an overview of these functional screening platforms, I will illustrate strategies of data integration that have enabled rapid discovery and translation of new targeted therapy strategies, and I will discuss our experience to date with direct clinical implementation of findings from these functional screening data.

Citation Format: Jeffrey W. Tyner. Functional genomics for discovery of pathogenic mechanisms of disease and novel therapies for hematologic malignancies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA04.

©2016 American Association for Cancer Research.
2016