Study uncovers two inhibitors to halt metaplastic breast cancer progression

A national study seeking more effective treatment for deadly metaplastic breast cancer has identified two inhibitor drugs with the potential to interrupt disease progression.

Houston Methodist and a team of researchers from across the country examined the biology of metaplastic breast cancer, comparing it to non-metaplastic triple negative breast cancer. They discovered metaplastic breast cancers typically exhibit two unique signaling pathways in their cell interaction. Researchers were able to disrupt these pathways using a class of inhibitors typically used to treat advanced cancers - phosphoinositide 3 kinase inhibitor (P13K) - in combination with a nitric oxide inhibitor (NOS) typically used to treat septic shock, cardiovascular disease and other conditions. When introduced to the cell, these drugs disrupted these pathways, making the treatment more effective.

A rare and aggressive form of disease, metaplastic breast cancer typically grows faster and is more likely to metastasize or spread to other parts of the body than other breast cancers. It is also more likely to recur after successful initial treatment. Patients with metaplastic breast cancer will often receive the same treatment as a patient with triple negative breast cancer, another aggressive and deadly form of the disease. However, metaplastic breast cancer often does not respond well.

The findings are in the article, "NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression," and published in Nature Communications, an online journal in the Nature family of publications. The study's corresponding author is Dr. Jenny Chang, the executive vice president, president and CEO, and chief academic officer at the Houston Methodist Academic Institute. She holds the Ernest Cockrell, Jr. Presidential Distinguished Chair at the Academic Institute and is former director of the Dr. Mary and Ron Neal Cancer Center at Houston Methodist.

"This is a significant finding because it offers a promising therapeutic option for one of the most aggressive and difficult-to-treat subtypes of breast cancer," said Chang. "We have the potential to improve outcomes for patients who currently face limited treatment options and poor prognoses, marking an important step forward in cancer research and therapy."

The first author, Dr. Tejaswini Reddy, hopes these findings will help develop a specific care plan for metaplastic cancer patients and improve long-term survival of the disease.

Our findings highlight a promising therapeutic combination that could hopefully change the landscape of metaplastic breast cancer treatment. Translating this research into a National Cancer Institute-funded clinical trial is crucial to improving outcomes for patients facing this rare and aggressive disease. Moreover, this approach may have broader implications, potentially benefiting patients with other cancers with similar biology."

Dr. Tejaswini Reddy, first author

The findings of this preclinical study have translated into a National Cancer Institute (NCI)-funded phase 2 clinical trial to help patients with this rare and aggressive malignancy (https://clinicaltrials.gov/study/NCT05660083).

Chang's collaborators on this study were: Tejaswini Reddy, Akshjot Puri, Liliana Guzman-Rojas, Christoforos Thomas, Wei Qian, Jianying Zhou, Hong Zhao, Bijan Majboubi, Andrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Roberto Rosato, Karina Ortega Martinez, Maria Florencia Chevaro, Camila Ayerbe, Noah Giese, David Wink, Stephen Lockett, Stephen Wong, Jeffrey Chang, Savitri Krishnamurthy, Clinton Yam, Stacy Moulder, Hele Piwnica-Worms, and Funda Meric-Bernstam.

This work was supported by NCI grants, the Breast Cancer Research Foundation, CREDO, NIAID, and philanthropic support from Dr. Mary & Ron Neal.