Triple-negative breast cancer (TNBC) is hard to treat, because it lacks three common markers for drugs to target. Now, instead of going after the tumors directly, a research team led by the University of Sussex in the U.K. has found a target in their surrounding environment and identified an existing blood cancer med as a possible treatment.
The researchers found that using Gilead Sciences’ FDA-approved Zydelig to target the PI3K pathway in the healthy tissues that surround cancerous cells could slow TNBC growth and reduce tumor metastasis in mice. They reported the findings in the Journal of Clinical Investigation.
Zydelig, approved by the FDA in 2014, was the first in the PI3K inhibitor approved to treat B-cell malignancies. It specifically targets the PIK3C-delta form of the PI3K enzyme. Activation of the PI3K/AKT/mTOR pathway is a known contributor to the development of multiple cancer types and resistance to treatments. Last year, the FDA approved Novartis’ PI3K inhibitor Piqray, which targets the PIK3C-alpha form of the enzyme, to be used alongside AstraZeneca’s older Faslodex to treat HR-positive and HER2-negative breast cancer.
After analyzing samples from TNBC patients, the University of Sussex researchers linked high levels of PIK3C-delta in cells known as fibroblasts—the most prominent cells in the tumor microenvironment—to poor patient survival. Cells lines cultured in lab dishes also showed increased TNBC invasiveness, even though the tumor cells themselves exhibited no changes in the PIK3C-delta protein. Interestingly, fibroblast PIK3C-delta in ER-positive and HER2-positive breast cancers didn’t correlate with survival outcomes.
To verify the effects of PIK3C-delta, the team tested Zydelig in two mouse models of TNBC. They observed a significant reduction in tumor growth following the treatment. Compared with control mice, animals that got Zydelig also saw significant decreases in the number of lung metastasis nodules.
Other research teams are turning to existing drugs for inspiration in tackling TNBC. In a new study published in Science Translational Medicine, a team led by Vanderbilt University found a role for the MYCN oncogene in TNBC. MYCN is a transcription factor in the MYC family, members of which regulate the expression of genes involved in cell growth, proliferation, metabolism and survival. Their abnormal expression has been found in neuronal or neuroendocrine tumors.
The Vanderbilt team showed that MYCN is also overexpressed in TNBC—and at a higher rate in cases that don’t respond to chemotherapy. Strategies to directly target MYCs have been unsuccessful, but the team found combining BET and MEK inhibitiors could work indirectly.
Adding Novartis’ FDA-approved MEK inhibitor Mekinist to a BET inhibitor—either Incyte’s INCB054329 or another drug called JQ1—led to a significant reduction of tumor growth in mice with MYCN-expressing TNBC patient-derived xenografts, the researchers reported.
“This study provides pre-clinical data for investigation of the potential utility of MEK and BET inhibitors in advanced triple-negative breast cancer,” Jennifer Pietenpol, the study’s senior author, said in a statement. “As a next step, our research team is proposing the further development and clinical trials of this combination therapy.”
The University of Sussex-led team also hopes its findings will spark interest in clinical trials of Zydelig or other PIK3C-delta inhibitors in TNBC.
“Our results suggest that repurposing already available drugs which act as inhibitors for [PIK3C-delta] could stop the progression of [TNBC],” Georgios Giamas, the study’s senior author, said in a statement. “As the drugs are already available and FDA approved, clinical trials could begin immediately to further investigate the use of these inhibitors for triple negative breast cancer treatment.”