Triple negative breast cancer (TNBC) remains the most aggressive and deadly type of breast cancer, but new findings from cancer researchers at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, are pointing the way toward therapeutic strategies that could be tested in clinical trials in the future. Using patient-derived samples in pre-clinical work, researchers discovered that by combining two therapeutic agents they could nudge TNBC cells into a more treatable state. Findings are published in Nature.
"When combined, these therapeutic agents can hijack signals that occur naturally in the body to eliminate breast cells after the cessation of lactation to kill these aggressive cancer cells," said senior author Karen Cichowski, PhD, of the Division of Genetics at Brigham and Women's Hospital (BWH). "Our results provide compelling support for the development of clinical trials to test whether combining these agents could benefit patients with TNBC."
Specifically, the researchers discovered that that by combining two types of agents known as EZH2 and AKT inhibitors, they could coax TNBC cells to differentiate. Once the cells are differentiated, these agents kill tumor cells by triggering a process similar to involution, which normally occurs when breast tissue returns to a non-lactating state after a mother stops producing breast milk. The researchers also used machine learning to predict patient responses—another step that could help set the stage for clinical trials in patients.
In future studies, the researchers are interested in exploring whether similar drug combinations may be effective in other tumor types.
Authorship: In addition to Cichowski, BWH authors include Amy E Schade, Naiara Perurena, Yoona Yang, Carrie L Rodriguez, Anjana Krishnan, Alycia Gardner, Patrick Loi, Yilin Xu, Van TM Nguyen, GM Mastellone, Natalie F Pilla, Marina Watanabe, Keiichi Ota, Rachel A Davis, Kaia Mattioli, Dongxi Xiang, Zhe Li, and Sandro Santagata.
Disclosures: Cichowski is an advisor at Genentech and serves on the scientific advisory board of Erasca, Inc. Disclosures for other authors can be found in the paper.
Funding: This work was supported by a grant from the Cancer Research UK Grand Challenge and the Mark Foundation for Cancer Research to the SPECIFICANCER team (KC) and a DOD BC201085P1 Transformative Breast Cancer Consortium Award.
Paper cited: Schade AE et al. "AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution" Nature DOI: 10.1038/s41586-024-08031-6
