New drug combinations could improve therapies for breast cancer and other aggressive cancers

Researchers at Oregon Health and Science University have identified a combination of promising treatments to slow cancer progression and reduce tumor growth. Their research lays the foundation for developing more effective treatments for triple-negative breast cancer and mesothelioma, two aggressive forms of cancer that are difficult to treat.

The new study was published Friday in Reports on medicine cells.

“Current immune therapies are effective for only a small percentage of patients with these types of cancer,” said Sanjay V. Malhotra, Ph.D., co-senior author of the study. Malhotra is the Sheila Edwards Lienhart Chair in Cancer Research, professor of cell, developmental and cancer biology, and co-director of the Center for Experimental Therapeutics at OHSU’s Knight Cancer Institute. “This is a serious gap in treatment, and new drugs are needed.”

Solid tumors, such as triple-negative breast cancers, called TNBC, and mesothelioma, a cancer that forms in internal organs, often do not respond to chemotherapy or certain immune therapies, such as checkpoint inhibitors, which are drugs that block checkpoint proteins to stimulate the body’s immune system so it can fight the cancer.

“Only a subset of patients, about 20 to 40 percent, with advanced solid tumors experience clinical benefit, and of those, a substantial portion progress over time,” said Shivaani Kummar, MD, one of the study’s authors. She is professor and chief of the division of hematology and medical oncology in the OHSU School of Medicine, co-director of the Center for Experimental Therapeutics, and co-deputy director of clinical and translational research at the OHSU Knight Cancer Institute.

“The ability to perform combination immunotherapy-based screening and rapidly advance promising combinations into clinical development could provide more effective therapies for patients with a variety of cancers,” she said.

Successful combination

The research team developed a cell-based test to identify molecules found in macrophages, a type of white blood cell that patrols the body for invading organisms. The researchers used the test to screen 1,430 small molecule drugs approved by the Food and Drug Administration to test combinations with immune checkpoint inhibitor therapy. The best candidates that improved response to checkpoint inhibitors were then tested in animal models of TNBC to identify those that slowed breast cancer growth.

“This combination worked on other breast cancer subtypes besides TNBC,” Malhotra said. “The drugs not only slowed the progression of the cancer, but also caused the cancer to regress, which is very exciting to say the least.”

The successful combination that slowed and shrank cancer in animal models involved standard chemotherapy, combined with a checkpoint inhibitor and the drug indomethacin, a nonsteroidal anti-inflammatory drug.

Lisa Coussens, Ph.D., chair of the OHSU School of Medicine’s Department of Cell, Developmental and Cancer Biology and co-deputy director of basic and translational research at the OHSU Knight Cancer Institute, is co-senior author of the study and an expert on the role of immune cells in regulating various aspects of solid tumor development.

“The study recognized the critical importance of macrophages that not only directly accelerate tumor progression but also suppress the activity of antitumor T cells,” she said. “Identifying these cells will lead to novel targeted therapies to stifle the suppressive T cell activities of macrophages in solid tumors. This approach can be combined with checkpoint inhibitors and chemotherapy to improve outcomes for patients with certain solid cancers.”

In the future, the collaborative team will test other drug combinations from their screening with chemotherapy and checkpoint inhibitors on different types of hard-to-treat solid tumors, such as mesothelioma, pancreatic tumors and melanoma.

“Our approach opens an underexplored area for studying immunotherapy with novel drug combinations,” Malhotra said. “With adequate resources, these new treatments could be evaluated in clinical trials within 18 to 24 months.”

Other contributors to this study included OHSU researchers Sushil Kumar, Ph.D., Dhanir Tailor, Ph.D., Arpit Dheeraj, Ph.D., Wenqi Li, MS, Kirsten Stefan, Ph.D., Jee Min Lee, MS, and Pepper Schedin, Ph.D., as well as Dylan Nelson, MS, and Bailey Keefe, MS of Oregon State University.