James M. Rae, PhD

Developing new treatments for anti-estrogen resistant ER-positive breast cancer.

Impact

Approximately 70 percent of patients with breast cancer have estrogen receptor (ER)-positive breast cancer. Drugs that block ER signaling are effective in the prevention and treatment of both early and advanced disease. However, nearly a third of patients with newly diagnosed ER-positive breast cancer receiving a currently approved anti-estrogen therapy will suffer a metastatic recurrence, and nearly all patients with ER-positive metastatic breast cancer (MBC) ultimately become resistant to all known anti-estrogen drugs and succumb to their disease. There is a critical unmet need to develop more effective drugs targeting ER-positive breast cancer.

Progress Thus Far

Mutations in the Estrogen Receptor 1 (ESR1) gene are found in over 30 percent of MBC and confer resistance to all anti-estrogen treatments. Protein degradation has emerged as an alternative drug design, especially for cancers. These drugs known as PROTACs not only target the protein of interest but destroy it though degradation. Dr. Rae and his team hypothesize that PROTACs designed to degrade normal ER and ESR1-mutant ERs will prove superior to current estrogen-targeted therapies and will revolutionize the treatment of breast cancers. Using start-of-the-art chemistry in collaboration with fellow BCRF Investigator, Dr. Shaomeng Wang, they have developed several PROTAC ER degraders and identified promising lead compounds to test in preclinical breast cancer models.

What’s Next

The team will test the efficacy of their lead compounds both as single agents and in combination with CDK4/6 inhibitors, the standard of care in metastatic ER-positive breast cancers. Successful completion of this project will lead to clinical trials aimed at expanding treatment options for patients with anti-estrogen resistant ER-positive metastatic breast cancer.