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Under the Microscope: New Combination Drug Therapies Could Mean Better Outcomes for Breast Cancer Patients

Successfully treating cancer depends on finding the right targeted drug therapies that kill cancer cells, but this process is complicated by the many varieties of cancer and the differences in how cancer cells interact with other cellular processes. One example is BH3 mimetics, a class of drugs that have proved effective against some kinds of cancer, such as leukemia and other blood cancers, but have been less effective in stopping the growth of solid tumors, including breast cancers.

With funding from the V Foundation for Cancer Research, Kris Wood, Ph.D., an assistant professor in the department of pharmacology and cancer biology at Duke University, set out to understand why some cancers appear to resist BH3 mimetics. By finding new combination therapies to overcome this resistance, his team is focused on opening new treatment options for breast cancer and other solid tumors.

Looking at failure to find a way to succeed

BH3 mimetics are designed to kill cancer cells and counter the resistance of cancers to chemotherapy treatments. They do this by inhibiting proteins in the BCL-2 family that protect cancer cells from dying when normal cells would. While BH3 mimetics successfully target these proteins in some cancers, they aren’t effective against all cancer types.

“My lab’s basic interest is in understanding why cancer drugs fail,” said Wood. “Our hypothesis was that something else was keeping BH3 mimetics from killing solid tumor cells.”

Assisted by doctoral student Grace Anderson (now a postdoctoral researcher at Stanford University), Wood first studied the effectiveness of a BH3 mimetic drug called ABT-737 in cell lines representing 10 different cancers. Results showed most solid tumor cancer lines were insensitive to ABT-737. Next, the team worked to identify drugs that could sensitize solid tumor cancers to BH3 mimetics, focusing on drugs that target signaling pathways known to inhibit the death of cancer cells.

If these pathways could be blocked, Wood hypothesized, it would free the BH3 mimetics to attack and kill the cancer cells.

 

When two (or more) drugs is better than one

The experiments led to an impressive result: when the BH3 mimetic drug ABT-737 was combined with other drugs designed to block a pathway known as mTOR, the effectiveness of the BH3 mimetics drug could be dramatically improved. The outcome was especially pronounced in breast cancer cells with mutations to the PIK3CA gene, a mutation found in about 35% of all breast cancer cases.

“We wanted to find out how we can better target solid tumors that don’t respond well to therapies, and found out that by combining BH3 mimetics with drugs that block the functions of other proteins, we could have much more success at treating solid tumors,” said Wood. “The evidence suggests that BH3 mimetics working with other drugs like mTOR inhibitors should work.”

The research also helped identify proteins that regulate the lifecycles of cells in breast cancer, specifically the proteins MCL-1 and BCL-XL. These insights could lead to new treatment strategies that directly or indirectly target these proteins in treatments for different cancer subtypes.

 

From laboratory experiments to clinical trials

Based on the work done in Wood’s lab, the U.S. Department of Defense funded clinical trials to study the effectiveness of drug combinations involving BH3 mimetics. These trials are now in the planning stage.

“Through clinical trials, we hope to show these new therapies can delay the growth of tumors in PIK3CA mutant breast cancer,” said Wood.

The V Foundation-funded research is translating into success on scientific and practical levels, according to Wood. First, it helped to answer the scientific question of why breast cancers with mutations to the PIK3CA gene fail to respond to current drug therapies designed to attack the cancer. Second, it opened the door to new, more successful therapies that could soon translate into better clinical care and better outcomes for a significant percentage of breast cancer patients.

“As a researcher, it is always meaningful to do work and make discoveries that teach you something about the science and add to the body of knowledge,” said Wood. “To have an impact on science while also being able to make a difference in terms of clinical treatments is especially gratifying.”