Research
Nuclear Receptors are small molecule-activated transcription factors and key drivers of cancer pathology. Because NR genomic activities are highly dependent on the binding of small molecules to reprogram the transcriptome, they are well ideal therapeutic targets for a diverse range of diseases. In fact, 16% of all FDA approved drugs target NRs. Our goal is to understand how small molecules influence NR structures, alter their genomic activities, and achieve breast cancer-specific therapeutic endpoints. These structures enable the rational design of improved therapeutic small molecules, which will be used as anti-cancer agents to address the unmet therapeutic needs of breast cancer patients.
Current Projects
Developing Novel Antiestrogens to Treat Drug-Resistant Hormone Receptor Positive Metastatic Breast Cancer
Estrogen receptor alpha (ERα)-targeted hormone therapies, based on tamoxifen or aromatase inhibitors, remain front-line adjuvant therapies to prevent luminal breast cancer metastasis. Unfortunately, after an average of 5-years, approximately 50% of patients present progressive hormone hormone-therapy resistant disease. Recently, somatic mutations to ESR1 (the gene for ERα) were identified in approximately 30-50% of hormone-resistant ER+ metastatic breast cancer patients. We have shown that improved antiestrogens are potent in this setting. Based on our x-ray crystal structures, we have synthesized a series of novel small molecules to overcome the impact of these mutations on therapeutic activity. The therapeutic potential of these compounds, alongside a library of other antiestrogens, are being evaluated in a unique platform with engineered breast cancer cell lines and mouse models.
Estrogen receptor alpha (ERα)-targeted hormone therapies, based on tamoxifen or aromatase inhibitors, remain front-line adjuvant therapies to prevent luminal breast cancer metastasis. Unfortunately, after an average of 5-years, approximately 50% of patients present progressive hormone hormone-therapy resistant disease. Recently, somatic mutations to ESR1 (the gene for ERα) were identified in approximately 30-50% of hormone-resistant ER+ metastatic breast cancer patients. We have shown that improved antiestrogens are potent in this setting. Based on our x-ray crystal structures, we have synthesized a series of novel small molecules to overcome the impact of these mutations on therapeutic activity. The therapeutic potential of these compounds, alongside a library of other antiestrogens, are being evaluated in a unique platform with engineered breast cancer cell lines and mouse models.
