Breast cancer (BC) is normally dependent upon the estrogen hormone that interacts with the estrogen receptor (ER) expressed in BC cells. Drugs designed to inhibit ER activity or block estrogen synthesis in the body are currently being used in the clinic to treat BC and have been quite successful in controlling breast cancer progression for the majority of patients. Regrettably, however, BC often becomes resistant to these endocrine therapies, leading to endocrine-resistant metastatic breast cancer (MBC), a very aggressive cancer that leads to death. Recent large-scale genomic studies have revealed that a series of activating mutations in the ER gene (ESR1) in endocrine-resistant MBC patients...
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Breast cancer (BC) is normally dependent upon the estrogen hormone that interacts with the estrogen receptor (ER) expressed in BC cells. Drugs designed to inhibit ER activity or block estrogen synthesis in the body are currently being used in the clinic to treat BC and have been quite successful in controlling breast cancer progression for the majority of patients. Regrettably, however, BC often becomes resistant to these endocrine therapies, leading to endocrine-resistant metastatic breast cancer (MBC), a very aggressive cancer that leads to death. Recent large-scale genomic studies have revealed that a series of activating mutations in the ER gene (ESR1) in endocrine-resistant MBC patients. Of these, Y537S and D538G mutations are found at a much higher rate in patients with MBC. Remarkably, these mutations produce an ER with much higher transcriptional activity in the absence of estradiol. Since a significant proportion of antiestrogen-resistant BC continues to be dependent on ER signaling, current therapies are unable to save these patients. Thus, it is a critical need to develop the next generation of antiestrogens, which inhibit ER mutant proteins in MBC to improve patient survival. The overall goal of this research proposal is to use our larger in-house DNA-encoded chemical libraries (DECLs) to identify and develop specific drug-like probes and nominate preclinical candidates to target ER mutant proteins and develop mutant-specific small molecule inhibitors for MBC patients. We anticipate that this project will provide yield new avenues of investigation for the development of future therapeutics to inhibit the growth of metastatic breast tumors in patients with ESR1 mutants. Successful completion of the studies outlined in this proposal could rapidly introduce a new drug for the treatment of mutant ER-positive MBC patients that have become unresponsive to current endocrine therapies.
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