Titles and Affiliations
Associate Professor of Internal Medicine
Associate Professor of Pharmacology
Research area
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. There is a critical unmet need to develop more effective drugs targeting ER-positive breast cancer. 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.
Progress Thus Far
Building on their earlier work developing potent, orally available PROTACs capable of degrading both normal and mutated ER, Dr. Rae and his team have developed several laboratory models of breast cancer cells that are resistant to these PROTAC ER degraders, including cells resistant to the recently FDA-approved PROTAC drug for ER-positive, ESR1 mutated advanced or metastatic breast cancer (vepdegestrant, Veppanu®). These models give the team a valuable tool for understanding how resistance to PROTAC-based therapies develops and how it might be overcome.
What’s Next
The team will use these resistant models to uncover the specific mechanisms driving resistance to PROTAC-based ER degraders. In parallel, they are developing a new class of PROTAC degraders that take a different approach. Rather than targeting ER itself, these compounds target two proteins that are critical to how ER drives breast cancer growth. Promising new drug candidates will be tested across multiple breast cancer laboratory models, including those with ER mutations and those resistant to PROTAC therapy. This research directly addresses anti-estrogen drug resistance, one of the most pressing challenges in breast cancer treatment, potentially expanding treatment options for patients with advanced disease who currently have few alternatives.
Biography
James M. Rae, PhD is a research scientist with principal expertise in breast cancer and studies multiple aspects of cancer pharmacology including novel drug development, metabolism, pharmacokinetics and dynamics, and genomics, and biomarker identification and characterization. He holds faculty appointments in the Department of Internal Medicine and the Department of Pharmacology at University of Michigan. He is involved in several large team science studies and has been a member of the National Cancer Institute’s (NCI) National Clinical Trials Network (NCTN) and the South West Oncology Group (SWOG) where he serves as the Executive Officer of Translational Medicine. He also serves on the NCTN Biospecimen Banks Group Banking Committee. He is a recognized expert in the field of breast cancer research with a primary focus on the pharmacology of drugs that antagonize estrogen receptor signaling.
