Saturday, September 14, 2024
9/14/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
