Hijacking cancer driver to activate cell death by chemically induced proximity

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Abstract Personalized targeted cancer therapy, while initially effective, leads to resistance and disease progression in >50% of patients in as rapidly as few months after initiating therapy. These therapies directly inhibit the catalytic and/or ligand-induced functions of the cancer driver, leading to resistance via mutational escape or epigenetic/transcriptional bypass. To address mutational escape, recent therapeutic approaches leverage Chemically induced Proximity (CiP): bifunctional molecules that recruit two proteins into proximity for an emergent therapeutic effect. However, current CiP-based therapies are limited to degradation, which suffers from similar feedback mechanisms of resistance as direct inhibition of the cancer driver. Then, we recognized that 45% of all cancer genes are direct transcriptional regulators. Therefore, this proposal outlines a novel CiP- enabled therapeutic paradigm to hijack cancer drivers to amplify a therapeutic transcriptional program to directly kill cancer cells. Specifically, the goal of this proposal is to hijack the estrogen receptor in breast cancer to drive overexpression of pro-apoptotic factors to induce cancer cell death. First, I will systematically define the most potent pro- apoptotic factors for transcriptional upregulation induced cell death across multiple estrogen receptor positive breast cancer cell lines. Second, I will identify and validate transcription factors that regulate these pro- apoptotic factors by integrating bioinformatic analysis with a high throughput transactivator inducible recruitment screen. Finally, I will demonstrate that estrogen receptor in breast cancer can be hijacked for targeted transcriptional upregulation by recruiting it to an endogenously tagged transcription factor regulator of potent pro-apoptotic factors and to a targeted dCas9. Together, I will identify and demonstrate that estrogen receptor can be inducibly recruited by CiP to a transcription factor regulator of pro-apoptotic factors to induce breast cancer cell death. The successful completion of the aims described will establish not only a novel therapeutic approach for estrogen receptor positive breast cancer but also a generalizable therapeutic paradigm across multiple cancer types with transactivating cancer drivers. Furthermore, I will identify robust candidates for subsequent therapeutic heterobifunctional molecule development. The proposal presented also reflects my training goals of becoming an interdisciplinary physician-scientist bridging chemical biology tools and epigenetic gene regulation to address critical problems and needs in cancer biology and therapy.