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Novel Combination Therapeutic Strategies to Ablate Resistance to Hsp90 Inhibitors

John Koren

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National Institutes of Health (NIH)
Hsp90 in cancer cells can stabilize mutated, oncogenic, and metastable proteins. This stability serves to maintain the oncogenic phenotype. Inhibition of Hsp90 can induce cell death through the destabilization of multiple pathways [1, 2]. This anti-cancer efficacy is the impetus for the 20-plus Hsp90 inhibitors presently under clinical investigation [3, 4]. However, clinical progress has been slow despite the cancer cell-specificity. We hypothesize that some tumor cells and cancer models have intrinsic death evasion mechanisms which allow for evasion from Hsp90 inhibition. Preliminary studies for inhibitors of such mechanisms identified ABT- 737 as a potent killer of cells which survived Hsp90 inhibition. ABT-737 inhibits the anti-apoptotic action of Bcl- 2 and Bcl-xl; two pro-survival proteins involvedin the intrinsic apoptosis machinery [5]. The combination of Hsp90 inhibitor and ABT-737 was extremely effective across all cell models tested and was, interestingly, sequence specific (ABT-737 kills Hsp90 inhibitor-surviving cells; Hsp90 inhibition after ABT-737 has no unique effect). As over twenty Hsp90 inhibitors are presently involved in clinical trials, strategies applicable tocells which evade Hsp90 inhibition could not be more timely. Using cell, animal, and patient derived tumor samples, the PI will set in motion plans to investigate the potential and underlying mechanisms of this therapeutic combination. The proposed training plan will investigate the clinical potential for a combination of an Hsp90 inhibitor, PU-H71, and ABT-737. Throughout the proposed experiments, the PI will be trained in novel techniques, be further educated in cancer biology, and learn from experienced clinicians and researchers how to transition a potential therapeutic strategy from bench to bedside. Novel experimental strategies will be employed to determine the mechanisms which allow for the sensitivity to the identified combination, but also to help predict and identify factors which allow for the initial evasion from Hsp90 inhibitors. Biochemical analyses of the cellular environments will be compared to observed combination sensitivities to determine the most critical survival machinery. Ultimately, these studies will provide insight into intrinsic therapeutic evasion, clarify the role of molecular chaperones in disease, and potentially generate a novel therapeutic strategy to enhance the efficacy of a potent anti-cancer agent.

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