Inhibiting Production of One Protein Restores Treatment Benefit in Resistant Breast Cancer

WASHINGTON (October 3, 2016) — A team of investigators led by researchers at Georgetown Lombardi Comprehensive Cancer Center has found, in animal models of human breast cancer, that inhibiting a single protein restores sensitivity to tamoxifen, a commonly used drug for treatment of some breast cancers.

Researchers say the findings, reported in the journal Cancer Research, also show that targeting the protein, glucose-regulated protein 78 (GRP78), toxically stresses breast cancer cells, and so could be an effective therapeutic option for all forms of endocrine-resistant breast cancer, and, possibly, other cancer subtypes.

“We believe that the strategy of silencing GRP78 would work with all other endocrine therapies used in the clinic, and may work in other types of breast cancer and other cancers,” says the study’s senior investigator, Robert Clarke, PhD, DSc, professor of oncology and Dean for Research at Georgetown University Medical Center.

“We found that silencing GRP78 does not allow breast cancer cells to effectively use their mitochondria — their power plants — and that alone can lead to cell death. However, adding tamoxifen to a GRP78 inhibitor offers an ultra effective, lethal double whammy to the most common form of breast cancer,” Clarke says.

He adds that this study potentially offers “a very promising advance” in breast cancer research to understand resistant cancer. About 70 percent of all breast cancers are estrogen-receptor positive (ER+), which means they depend on estrogen to grow. In many of these cancers, treatment involves preventing estrogen from reaching the cancer cell. However, about 50 percent of treated tumors develop resistance to hormone blocking treatments.

GRP78 inhibitors have already been developed and are being tested in preclinical studies for other conditions, but for this research, Georgetown investigators created their own GRP78 inhibitor.

The Georgetown researchers have long been studying the role of GRP78 in ER+ breast cancer. In 2012, they reported, for the first time, that GRP78 regulates resistance to tamoxifen as well as fulvestrant, another endocrine therapy, and that it can control the death of breast cancer cells in the laboratory.

In this study, they investigated cellular mechanisms of GRP78 in a living model of breast cancer — mice implanted with human ER+ breast tumors.

Investigators found that GRP78 plays another crucial role — that of regulating the cell’s metabolism of lipids (fats). As GRP78 levels increase, mitochondria in the cancer cell escalate their burning of fats to provide energy and new growth, says the study’s lead researcher, Katherine Loree Cook, PhD, who was a postdoctoral fellow in Clarke’s lab at the time of the study and is now an assistant professor at Wake Forest University.

But when their drug inhibited GRP78 protein production, the level of polyunsaturated fatty acids (PUFAs) increased inside cancer cells because the fat was not being burned inside mitochondria.

A build-up of PUFAs inside the cells produces an immune response targeting the cancer cells for destruction.

“So not only is GRP78 inhibition reducing the ability of a cell to produce energy, it is flagging recruitment of immune cells whose job is to chew up the cancer cell,” says Cook.

Finally, the team observed that using a GRP78 inhibitor and tamoxifen “enhances the effectiveness of tamoxifen in tumors that were already sensitive to the drug,” Cook says.

Clarke say this same response might be possible with drugs that treat breast cancers not powered by estrogen — as well as other tumor types. “Studies have found that GRP78 overexpression promotes resistance to several cancer chemotherapies, used for breast cancer and other tumors. Therefore, GRP78 inhibition may be beneficial for the treatment of other types of chemotherapeutic resistant tumors,” Clarke says.

He adds that the research team is studying the approach in other animal models before moving into human studies.

Co-authors include David R. Soto-Pantoja, of Wake Forest University School of Medicine; David D. Roberts, from the National Cancer Institute, and from Georgetown Lombardi: Pamela A. G. Clarke, M. Idalia Cruz, Alan Zwart, Anni Warri, and Leena Hilakivi-Clarke.

The work was supported by a DOD Breast Cancer Research Program Postdoctoral Fellowship (BC112023), a NCI Career Transition Award (1K22CA181274-01A1), awards from the US Department of Health and Human Services (R01-CA131465, U01-CA184902 and U54-CA149147), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Clarke, Cook and the other co-authors report having no personal financial interests related to the study.

About Georgetown Lombardi Comprehensive Cancer Center

Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute as a comprehensive cancer center — the only cancer center of its kind in the Washington, DC area. A part of Georgetown University Medical Center and MedStar Georgetown University Hospital, Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).

About Georgetown University Medical Center

Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC on Facebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).