Researchers have published a study describing how chemotherapy and a drug used to treat cardiac failure is able to regress tumor growth of patients with triple negative breast cancer.
Researchers at Houston Methodist Hospital have published a study describing how chemotherapy and a drug commonly used to treat cardiac failure is able to regress tumor growth of patients with triple negative breast cancer and prevent it from further spreading.
Researchers led by Jenny Chang, director of the Cancer Center at Houston Methodist and Emily Herrmann Presidential Distinguished Chair in Cancer, published the study from a Phase I/II trial in locally advanced breast cancer (LABC) and metastatic triple-negative breast cancer (TNBC) that demonstrated an overall response rate (ORR) of 45.8%. It was particularly impressive for the LABC cohort, with an ORR of 81.8%. For the TNBC cohort, the ORR was 15.4%. It was published in Science Translational Medicine.
Triple negative breast cancers refer to breast cancers that are negative for estrogen and progesterone receptors, and excess HER2 protein. Usually, they grow and metastasize quickly and there are limited treatment options.
The treatment is an inducible nitric oxide synthase inhibitor (L-NMMA) combined with chemotherapy drug taxane. The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in TNBC. Previous studies have found that inhibiting the iNOS signaling pathway using L-NMMA decreased tumor growth and improved survival.
“This is an effective way of cutting short drug development and getting it into patients as quickly as possible. This process has taken us less than five years and saved billions of dollars, giving us the opportunity to provide this new therapy faster for our patients,” Chang said.
Chang and her research colleagues identified variants in the RPL39 gene. L-NMMA, which was developed at Houston Methodist as a cardiac drug, along with taxane, was effective in cancers that were resistant to chemotherapy. This is a patient group that has about a 25% to 30% change of responding to onco-immune therapies, but the patients in their studies treated with L-NMMA demonstrated an overall response rate close to 50%.
Chang and her team are planning multi-national Phase III clinical trials to test L-NMMA in more patients. Chang recently received a $25 million gift from Dr. Mary and Ron Neal to expand the cancer center, which will be renamed in their honor. The Houston Methodist Hospital has plans to raise another $12 million in matching funds for the center’s research and related programs.
“The Neals are very generous,” Chang said. “They believe in our research and what we are doing.”
Chang’s research focuses on developing treatments for TNBC. She notes that immunotherapy drugs are somewhat effective in these patients, but the response rate is still low. In her research, she is testing the tumor microenvironment to try to identify ways to improve the response rate. In addition to L-NMMA, she is researching why breast cancer stem cells survive chemotherapy, radiation and hormone therapy.
She says that while working with cancer patients earlier in her career, the women with TNBC received chemotherapy. “It would work for a while, but then the cancer would regrow in an aggressive way — often more aggressively. That was before we understood genes.”
During her research, she narrowed 700 possible genetic markers down to two. In a 2017 study, Chang and colleagues found that RPL39 and its gain-of-function mutation A14V have oncogenic activity in TNBC, but that it can be mediated by iNOS. The most recent publication confirms those findings in breast cancer patients and demonstrates a promising approach to treating chemotherapy-resistant cancers.
