In just under four years, researchers have identified the gene involved in the development of metaplastic breast cancer — the most aggressive type of triple-negative breast cancer — and advanced a potential treatment for the disease to clinical trials.
“We not only uncovered the biological pathway stimulating cancer growth, but we found a compound that blocked it, increasing the survival of mice carrying human metaplastic breast tumors,” Jenny C. Chang, MD, director of the Houston Methodist Cancer Center, and the study’s senior author, said in a news release.
While metaplastic breast cancer accounts for less than 1 percent of all breast cancer, it is the most aggressive type of triple-negative breast cancer, and the odds of patients surviving are low.
A key reason is that metaplastic tumors are highly unresponsive to chemotherapy.
Only 40 percent of those who get the disease survive for three years. The survival rate for triple-negative breast cancer patients as a whole is 70 percent.
Triple-negative cancers test negative for estrogen receptors, progesterone receptors, and HER2. If a cancer has any of the receptors, it can be targeted with hormone therapies that block the pathways the receptors activate.
Researchers found that 39 out of 40 metaplastic breast patients have a mutation in their RPL39 gene that promotes tumors in the same way HER2 does. The mutated RPL39 cells divide uncontrollably, sparking tumor growth.
The identification of the mutation, which is common in virtually all metaplastic breast cancers, led the researchers to hypothesize that blocking the RPL39 pathway could prevent tumor growth.
The team discovered that RPL39 activated a protein called inducible nitric oxide synthase (iNOS). When levels of both proteins were elevated, patients had lower survival rates. This prompted the researchers to think that blocking iNOS would be a way to treat metaplastic breast cancer.
They found that L-NMMA, a compound that inhibits iNOS, reduced tumor volume in metaplastic breast cancer mouse models. They also learned that a combination of L-NMMA and Taxol (docetaxel), a chemotherapy drug, reduced tumor volume more than Taxol alone.
“The results showed elimination of the cancer in nearly all of the mice when combined with standard chemotherapy,” said Chang, who is also a professor of medicine at Weill Cornell Medicine. “Our goal is to turn metaplastic breast cancer from a debilitating disease into a chronic illness.”
L-NMMA will now be assessed in a Phase 1 trial of metaplastic breast cancer patients. The study, which is currently enrolling patients, will be conducted at Houston Methodist Hospital.
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