A team of researchers led by Duke Cancer Institute scientist Donald McDonnell, PhD, has been awarded a Breast Cancer Research Program (BCRP) Innovator Award, totaling $7,368,485, by the United States Department of Defense Office of Congressionally Directed Medical Research Programs (CDMRP).
The ultimate goal of the four-year translational project, “Cancer Cell Intrinsic and Extrinsic Actions of Steroid Hormones in Breast Tumors,” is to develop strategies to improve the effectiveness of existing and emerging endocrine therapies taken to prevent breast cancer recurrence by women whose breast cancer is ER-positive (estrogen receptor-alpha), the most common type of breast cancer.
Physicians, scientists and staff, 13 in all, from multiple departments at Duke and two scientists from UNC Chapel Hill will partner to define the impact of these endocrine therapies on immune cell function and tumor immunity in new and established animal models of breast cancer as well as in breast cancer patients, and turn their discoveries into the development of better-targeted next generation endocrine therapies.
“Endocrine therapy has had a very significant impact on long-term outcomes for breast cancer patients,” said principal investigator McDonnell, who chairs the Department of Pharmacology and Cancer Biology and co-directs the Duke Cancer Institute Women’s Cancer Research Program. “The drugs work very well, but our goal is for the drugs to be outstanding. We want to know, can we do even better?”
The strategy for battling estrogen receptor-positive breast cancer has, for several decades, been to reduce the amount of estrogen or inhibit the actions of estrogens in the woman’s body McDonnell explained. Starting in the mid-70s, small molecules that either inhibit the production of estrogen or block the binding of estrogen to the receptor within the cancer cell, have been the weapons of choice. McDonnell has even contributed to developing these drugs that, in his words, “beat the living hell out of the estrogen receptor.”
This approach is backed up by data showing that when estrogen is inhibited — by taking tamoxifen, an estrogen modulator, or aromatase inhibitors such as letrozole (for five years as a maintenance therapy following initial treatment) — there’s a decreased rate of breast cancer recurrence.
There are 1.5 million women currently on endocrine therapies in the U.S. for all stages of breast cancer. Patients with the best prognosis, who take endocrine therapies, have only a one-to-four percent chance, per year, that the disease will recur, said McDonnell. This means, however, that after 10 years, there could be as much as a 40 percent chance the cancer will come back. In the metastatic setting, endocrine therapy remains palliative. McDonnell wants to do better by all these patients.
The impetus for the DOD project is McDonnell’s theory that extreme estrogen deprivation could potentially have long-term negative consequences on the immune system, and thus for breast cancer outcomes.
Cancer cells aren’t the only ER-positive expressing cells. Immune cells also express estrogen receptor-alpha, which can actually be beneficial for the prevention of breast cancer, McDonnell explained, citing a 2002 study of 8000 post-menopausal women, called the Women’s Health Initiative, that found that those who took estrogen alone (hormone therapy) had a 35 percent decreased risk of breast cancer.
“There’s an urgent need to understand the impact of existing endocrine therapies on immune cell function and regulation,” said McDonnell. “Whereas current therapies may slow down the growth of tumors, they could be having a negative effect on the immune system, which could make the millions of women on these drugs more vulnerable to cancer recurrence.”
The research team will follow, for two years, 200 women with ER-positive breast cancer, beginning when they start the endocrine therapy (following surgery, radiation, and chemotherapy). They will assess in the lab whether there is a positive, negative or neutral effect on their immune system. The clinical study will be run out of Duke Cancer Center by Sarah Sammons, MD. The preclinical work will be done in the McDonnell Lab, and the drug development work will be a collaboration with researchers at the University of North Carolina at Chapel Hill.
“I can’t even tell you how excited we are about this project,” said McDonnell, who’s been the recipient of about a dozen DOD grants since he came to Duke in 1994. “I’m shifting resources from all these other projects because I think that this is one of those projects that will really change the field if we’re right.”
Though McDonnell will be hiring additional personnel in the months to come, including from other institutions, the initial assembled team includes from Duke: Sarah Sammons, MD; Kent Weinhold, PhD; Luigi Racioppi, MD, PhD; John Norris, PhD; Ching-yi Chang, PhD; Suzanne Wardell, PhD; Debarati Mukherjee, PhD; Binita Chakraborty, PhD; Kendall Tavares and Robert Baldi. Patient advocates Vernal Branch and Eva May will help advertise and recruit patients for the clinical study. Tim Willson, PhD, and Charles Perou, PhD, are the UNC Chapel Hill collaborators.