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.