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Abstract
Abstract Large-scale genomic profiling efforts, such as The Cancer Genome Atlas (TCGA) have painted an unprecedentedly detailed picture of the genetic alterations that underlie carcinogenesis, yet the key challenge remains as to how to turn this information into actionable therapies. Genomic deletions are a frequent event in diverse cancers, which inactivate a limited number of tumor suppressor genes (“driver”-events) but frequently include many chromosomal neighbors as “passengers”, some of which play critical but redundant roles in normal cellular housekeeping. The overall hypothesis we propose to test is that collateral deletions of such “passenger” genes can be utilized as novel targets of synthetic lethality, an idea which we term “collateral lethality." The large number of passenger deleted genes, playing diverse functions in cell homeostasis, offers a rich repertoire of pharmacologically targetable vulnerabilities presenting novel opportunities for the development of personalized anti-neoplastic therapies. We have provided in vitro proof-of-principal of a collaterally deleted glycolytic gene Enolase 1 (ENO1) at the 1p36 tumor suppressor locus in glioblastoma (GBM), that leads to dramatic sensitization to inhibition of the redundant paralogue, ENO2. The next step is to take this concept to the clinic. Our overall goal is to generate a clinical candidate Enolase inhibitor for tumors with ENO1-deletions, like GBM for which there is no other treatment option and the therapeutic benefit could be quite substantial. Citation Format: Yu-Hsi Lin, Naima Hammoudi, Nikunj Satani, Jeffrey Ackroyd, Sunada Khadka, Dimitra Georgiou, Joe Marszalek, Yuting Sun, Marina Protopopova, Maria E. Di Francesco, Barbara Czako, Alan Y. Wang, Ronald A. DePinho, Florian L. Muller. Collateral lethality: A new target for personalized oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2831.
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