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Duke Researchers Propose Combination Therapy for PIK3CA-Mutant Breast Cancer

NEW YORK (GenomeWeb) – A Duke University team has found early evidence that breast cancer cases marked by PIK3CA mutations may be vulnerable to combined treatments targeting programmed cell death and mTOR signaling pathways.

By screening small molecules on dozens of cell lines from 10 cancer types, the researchers searched for compounds that could bump up the apoptotic effects of so-called BH3 mimetic treatments such as the investigational drug ABT-737 (Active Biochem's experimental cancer drug Navitoclax). Their findings, published today in Science Translational Medicine, suggest that a combination of BH3 mimetics and mTOR pathway inhibitors can prompt a response in breast cancers with PIK3CA mutations, which occur in more than one-third of new breast cancer cases.

"Our preliminarily findings suggest that this therapy may be a safe and effective approach in human breast cancer patients who carry this mutation," senior author Kris Wood, a pharmacology and cancer biology researcher at Duke, said in a statement.

Because at least some successful chemotherapies have been developed by exploiting compounds that successfully induce apoptosis, the researchers reasoned that there might be yet-untapped ways to kick off apoptosis in cancer cells by meddling with proteins such as BCL-XL, BCL-2, or MCL-1 that typically stave off this programmed cell death.

In their effort to identify new treatment strategies involving such approaches, the investigators focused on ABT-737, an inhibitor that targets the BCL-2/BCL-XL anti-apoptotic proteins. In 43 cell lines from 10 cancer types that were exposed to the drug, they found acute myeloid leukemia cell lines that appeared to be sensitive to the drug.

The team expanded its search to include hundreds of cell lines from the Cancer Cell Line Encyclopedia, again detecting sensitivity to BH3 mimetics in blood cancers that was largely lacking in cells from solid tumor types.

But that changed when the researchers added in additional drugs targeting additional apoptosis-related signaling pathways. They found that at least a few breast cancer lines became vulnerable to ABT-737 in the presence of the PI3-kinase/mTOR pathway inhibitor BEZ235. Other cell lines, including a handful of colorectal cancer cells, became more susceptible to BH3 mimetics when sensitized by ERK pathway inhibitors.

The team delved into such effects in more detail. In a set of 19 more cancer lines, for example, it found that response to combination mTOR and BH3 mimetic treatment was more pronounced in forms of breast cancer with PIK3CA mutations.

Moreover, in their experiments with triple-negative breast cancer xenograft models, the researchers found that relatively low doses of ABT-737 and the mTOR inhibitor BEZ235 could shrink tumors in ways that the drugs did not when used on their own. Based on their follow-up experiments, they suspected that this effect might reflect apoptosis priming in the PIK3CA mutant breast cancers.

"One of the compelling results of the study is that we can use very low doses of both therapies to achieve strong results," lead author Grace Anderson, a graduate student in Wood's Duke lab, added, noting that it might be possible to curb some side effects by dialing down drug doses.

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