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Enhancing the efficacy of BH3 mimetics in blood cancers


Evasion of cell death is one of the hallmarks of cancer that has only recently become targetable using small molecule inhibitors. By antagonizing the pro-survival function of BCL-2 family proteins, these so-called BH3 mimetics skew cells towards undergoing apoptosis. Though single-agent approaches have yielded promising clinical efficacy in some contexts, it is often insufficient to induce substantial patient responses. This dissertation investigates the potential of using rational targeted therapies to enhance the efficacy of BH3 mimetics. In Chapter 2, we pursue the simple hypothesis that targeting a pathway whose aberrant activation is associated with cancer (the PI3K/AKT/mTOR pathway) can sensitize cells to BCL-2 inhibition. We demonstrate that inhibitors of this pathway synergize strongly with two BH3 mimetics, ABT-263 and ABT-199, and that the extent of this synergy can be predicted using dynamic BH3 profiling. By suppressing AKT activity, PI3K pathway inhibitors induced mitochondrial accumulation of pro-apoptotic proteins. This work provided insight into markers of pharmacodynamic response, tools for predicting efficacy, and evidence warranting further investigation. In Chapter 3 we pursue an alternative approach: that targeting a key metabolic pathway for which inhibitors are already FDA-approved, can also sensitize cells to BH3 mimetics. We show that targeting HMG-CoA reductase using statins selectively primes cancer cells for apoptosis and enhances the efficacy of ABT-199 in vitro and in vivo. We build on the work from Chapter 2 to demonstrate the predictive capabilities of dynamic BH3 profiling in cell lines and primary patient samples. Additionally, we identify downstream targets contributing to the sensitization effect, supporting further investigation. Lastly, in Chapter 4, I present incomplete or unpublished data that follows up on the work presented in Chapters 2 and 3. I also discuss potential future directions derived from those experiments as well as the implications of this work.

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