Research led by University of Colorado Cancer Center members points to a combination of drugs as a potential treatment option for a type of aggressive breast cancer.
Todd Pitts, PhD, and Jennifer Diamond, MD, co-authored a paper, published on March 1 in the journal Breast Cancer Research, on their study of ways to overcome resistance to doxorubicin, a type of chemotherapy drug that slows or stops the growth of cancer cells, in treating triple-negative breast cancer.
Overall, breast cancer is the most common cancer in women in the United States, and the No. 2 cause of cancer death in women (after lung cancer), although death rates have been declining since 1989, in part due to earlier screening and better treatments. According to the American Cancer Society, five-year survival rates across all breast cancer types range from 99% for localized cancers to 31% for breast cancer that has spread throughout the body.
Limited treatment options
Triple-negative breast cancer accounts for 15% to 20% of all breast cancer cases. It grows quicker and is more likely to return after treatment than other types of breast cancer, so survival rates are generally not as high.
“It’s a very aggressive subtype of breast cancer that tends to metastasize and become resistant to even standard-of-care chemotherapy agents,” says Pitts, associate professor of medical oncology in the CU Department of Medicine. Also, unlike other breast cancer types, hormone therapy is not an option for treating triple-negative breast cancer because its cells lack receptors (molecular connection points on a cell) for the hormones estrogen and progesterone.
That leaves a limited arsenal of treatment options for late stage triple-negative breast cancer. Doxorubicin “is probably the most common chemotherapeutic agent given to patients with triple-negative breast cancer,” Pitts says.
Doxorubicin is a type of chemotherapy drug called an anthracycline that slows or stops the growth of cancer cells by blocking an enzyme that cancer cells need to divide and grow. But triple-negative breast cancer can resist the effects of doxorubicin.
“One of the common resistance mechanisms for doxorubicin is what's called senescence, which causes cells to stop dividing and stay in a stable state. That can be a good thing if it means tumors aren’t growing, but it’s not always good, because senescent cells can release factors that will enhance the growth of nearby tumor cells,” Pitts says.
Triggering cell death
So Pitts and Diamond, and research assistant Stephen Smoots, investigated whether using doxorubicin along with a drug developed by University of Colorado Boulder researchers, called bocodepsin, would help reverse senescence and lead to apoptosis, a process of cell death that can be blocked in cancer cells. Bocodepsin is being studied as a treatment for other cancer types, including a subtype of melanoma.
Bocodepsin is a kind of drug called a histone deacetylase (HDAC) inhibitor that causes a chemical change that stops tumor cells from dividing. Bocodepsin is designed to be an upgrade from other HDAC inhibitors that’s more tolerable and potent.
The Pitts-Diamond study involved testing the drugs on cell lines from the CU Cancer Center’s Cell Technologies Shared Resource and other sources, with analysis performed by the cancer center’s Flow Cytometry Shared Resource.
“We found that when doxorubicin causes triple-negative breast cancer cells to go into senescence, and when you add bocodepsin to those senescence cells, those cells ended up inducing apoptosis,” Pitts says.
Hopes for a clinical trial
The study concludes that doxorubicin and bocodepsin are “a promising combination to overcome doxorubicin resistance in triple-negative breast cancer. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors, supporting the feasibility of evaluating this combination in patients with triple-negative breast cancer.”
Pitts hopes that the preclinical study will lead to a clinical trial for use of the two drugs in treating triple-negative breast cancer.
Pitts’ lab focuses on research into therapies for gastrointestinal (GI) cancers such as colorectal and pancreatic cancers, while the focus of Diamond’s lab is on breast cancer, especially triple-negative breast cancer. Pitts says he and Diamond share lab space and have collaborated for years. He notes that he runs a lab in the Division of Medical Oncology that focuses on getting research to the patients that it could help.
He adds: “We haven't looked at this specific combination in treating GI cancers because doxorubicin is not used for those cancers. But there is potential for bocodepsin to be used in combination with chemotherapies for other tumor types.”
Images at top: Staining of a triple-negative breast cancer cell line shows differences in senescence in the cells with no treatment (left), treatment with doxorubicin alone (center) and treatment with a combination of doxorubicin and bocodepsin (right) after six days of drug treatment. Senescent cells can release factors that enhance the growth of nearby tumor cells. Images were taken at x20 magnification. Images courtesy Todd Pitts, PhD.
