William G. Kaelin, Jr., MD

Identifying novel treatment strategies to block estrogen-driven breast cancers.

Impact

Most breast cancers require estrogen to grow. Drugs such as fulvestrant, tamoxifen, and aromatase inhibitors block estrogen-driven growth and are effective treatments for estrogen-receptor (ER)-positive breast cancers. Fulvestrant is unique in that it acts by degrading the estrogen receptor on cancer cells. The mechanism by which fulvestrant does this has been a longstanding mystery that Dr. Kaelin is focused on solving. As part of this work Dr. Kaelin’s team is seeking novel drugs that will degrade otherwise “undruggable” proteins that drive breast cancer growth. Leveraging their recent discoveries related to kidney cancer (a cancer that is highly responsive to immunotherapy), Dr. Kaelin’s team is also conducting studies to identify strategies to make breast cancers more easily recognized by the immune system. Collectively, these studies will provide new insights into the action of agents like fulvestrant that may be applicable to other target proteins and ways to improve response to immunotherapy in breast cancer—insights that will ultimately inform the development of better therapies to treat ER-positive breast cancer.

Progress Thus Far

The protein beta catenin promotes the growth of many cancers, including breast cancer. Dr. Kaelin previously developed a new technology to look for chemicals that could inactivate proteins that have historically been viewed as “undruggable” because of characteristics of their structure or function that makes them difficult to target. Nature produces far more diverse chemicals than can be synthesized by human chemists. The team, therefore, used their technology to analyze tens of thousands of mixtures of natural chemicals derived from various natural sources (for example, from plants) for beta catenin inactivators. They identified dozens of mixtures that could degrade or otherwise inactivate beta catenin in cells, then determined the active chemicals from mixtures capable of inactivating beta catenin.

For their work making breast cancer more recognizable to the immune system, the team found that HIF protein, which is characteristically overactive in kidney cancers, reawakens dozens of latent viruses called endogenous retroviruses (ERVs). Once activated, SRVs produce protein fragments that are then displayed on the surface of the cancer cells and recognized by cancer fighting T cells. They found T cells in kidney cancer patients that responded to immunotherapy that specifically recognized such ERV-derived protein fragments. HIF is often high in solid tumors, especially triple-negative breast cancers. Dr. Kaelin and team found that ERVs are activated in some breast cancers and can be super-activated with drugs that stimulate HIF activity. They used genetic approaches to look for genes in normal cells that are activated under high-HIF conditions.

What’s next

In the coming year, Dr. Kaelin and team will continue these projects to uncover new therapeutic and diagnostic strategies for breast cancer. The team will complete a screen targeting beta catenin to find compounds that inactivate it and investigate how. They will investigate the presence of ERV-derived protein fragments on breast cancer cells with varying HIF activity and assess response to immune therapies.