As one of the world’s leading experts in the science of estrogen receptor signaling and a pioneer in the development of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), Donald McDonnell, PhD, says one of the questions he is asked most frequently is which of these two completely different classes of ER modulator is most suitable and most likely to work best in metastatic breast cancer.

“The answer is maybe ‘yes’ — both may actually be effective, but for different reasons,” he said.

Dr. McDonnell, Co-Director of the Women’s Cancer Program at the Duke Cancer Institute, Duke University School of Medicine, discussed current research and future directions in the study of ER modulators when he delivered the Susan G. Komen^® Brinker Award for Scientific Distinction in Basic Science Lecture during SABCS 20.

Dr. McDonnell is being honored for his significant contributions to breast cancer research, which have provided critical insights into the structure, function, and regulation of nuclear hormone receptors and is helping to lay the foundation for the development and clinical use of novel endocrine therapies to treat ER+ breast cancer.

Currently, he said there are 12 SERMs and SERDs in development for metastatic breast cancer involving molecules that directly target the estrogen receptor.

“In breast cancer, this is most notably the estrogen receptor alpha, one of the two genetic forms of the estrogen receptor,” Dr. McDonnell said. “These molecules can either bind and competitively inhibit the receptor or can actually lead to the downregulation of the receptor.”

Researchers are now turning their attention to not only the receptor, but the receptor in complex with its obligate co-regulators, he said, noting that recent study findings have shown that interference with estrogen receptor signaling can be achieved not necessarily by targeting the receptor, but by targeting either the interaction of the receptor with its coactivators or the functionality of the coactivators.

“Indeed, molecules that actually do that are currently in late preclinical development for cancers,” Dr. McDonnell said.

Importantly, he said that researchers are beginning to understand that not all SERMs and SERDs function the same way in immune cells.

“Some of the SERMs and SERDs are having very positive effects on immune cell function, and some of them are actually having negative effects on immune cell function,” he said. “And so the goal of a project that we’ve got ongoing right now is to define the molecular characteristics of a compound that retains its cancer cell intrinsic activities, and is either neutral or at least not harmful in immune cells, but actually could be beneficial.”

Dr. McDonnell and his group have begun a clinical study looking at the extent to which immune cell function and repertoire are being affected by current standard-of-care endocrine therapies.

“I believe that we’ve made significant progress, but I think I can tell you that the current endocrine therapies are not optimized for use if we’re trying to manipulate the tumor environment,” he said. “I think it’s incumbent upon us in developing the next generation of endocrine therapies that we understand whether we’re having positive or negative effects when we give endocrine therapies to the whole tumor as an organ, and then use that information to develop the next generation of antagonists.”

SABCS registrants have exclusive on-demand access to Dr. McDonnell’s lecture, “SERMs or SERDs for Metastatic Breast Cancer… YES May Be the Answer,” and other virtual SABCS programming until March 13, 2021.