Researchers have shown that adding an experimental agent to chemotherapy is a promising novel strategy for treating some triple-negative breast cancers (TNBCs). Called triple-negative because it lacks three key cancer drivers (estrogen and progesterone receptors and the HER2 protein), TNBC cannot be treated with current hormone receptor or HER2-targeted therapies. With few other options, it is imperative for researchers to identify and define novel targets that can improve outcomes for people with TNBC.
In a first-in-class phase 1/2 clinical trial, BCRF investigator Dr. Jenny Chang and her colleagues showed that when combined with chemotherapy, the agent, L-NMMA can effectively treat TNBC that is locally advanced (in the breast) or metastatic (spread to other organs) and has resisted chemotherapy.
While early in the process of gaining approval for use in breast cancer, these results show great potential for this therapy combination as a novel and much-needed option for effectively treating TNBC.
The years-long process to get L-NMMA to clinical trial
L-NMMA (NG-monomethyl-L-arginine) blocks an enzyme called nitric oxide synthase that is important in cellular metabolism. L-NMMA was first used to treat cardiogenic shock (when the heart is unable to pump enough oxygen-rich blood to other organs). As with other clinical trials and new treatments doctors use today, the story of L-NMMA and its path to breast cancer clinical trials is a good example of how years of laboratory research is translated into the clinic—and, more specifically, following years of other basic research into how cancer cells evolve to resist therapies.
In 2009, researchers published results showing that while therapies can eliminate many cells within a tumor, breast cancer stem cells (first discovered by BCRF investigators in 2003) can survive and reinitiate tumor growth, leading investigators to ask how this process happens. Focusing on this question, Dr. Chang and her team reported their findings in a series of publications beginning in 2014: They identified two genes (RPL39 and MLF2) that play a role in breast cancer stem cells’ renewed activity and metastasis. In addition, they found that these genes are regulated by increased levels of inducible nitric oxide synthase, iNOS. Separate studies demonstrated that an increase in iNOS activity was associated with a poor prognosis in several cancers.
These findings pointed researchers in the direction of iNOS as a potential target for breast cancer treatment. Laboratory studies by Dr. Chang’s group showed that elevated iNOS was correlated with metastasis and poor survival in TNBC tumor models. Furthermore, these tumors resist chemotherapy by influencing iNOS metabolism.
Researchers then asked if blocking iNOS would reduce tumor growth—L-NMMA then emerged as a good candidate to test this question based on its anti-iNOS activity. In laboratory studies, Dr. Chang’s team demonstrated that adding L-NMMA to a taxane (a chemotherapy agent) was, in fact, better at reducing tumor growth and lung metastases than the taxane alone.
Next: A phase 1/2 clinical trial with L-NMMA
The success of these pre-clinical studies led Dr. Chang to design a clinical trial that could test the efficacy of the combination in patients, specifically those with advanced or metastatic TNBC that was not effectively treated with chemotherapy drugs alone. The team was also seeking to determine the mechanism by which L-NMMA could enhance the response to chemotherapy.
This trial enrolled patients from July 2016 through September 2021. As in any phase 1 trial, it was designed to determine the best dosing strategy to achieve maximum effectiveness with minimal side effects—information that informed the follow up phase 2 trial. Throughout the trial, the team observed how people reacted to the drugs and looked for potential toxicities, then they performed initial analysis to understand how the agent worked in breast cancer patients.
For this trial, investigators took advantage of the fact that L-NMMA was previously approved by the FDA for other uses. This meant that L-NMMA had already been through the FDA’s rigorous regulatory reviews and could be fast-tracked for use in this breast cancer clinical trial.
Then: The phase1/2 clinical trial showed promising results
The overall response rate (the proportion of patients that had some response) to L-NMMA in combination with a taxane was 45.8 percent. Locally advanced breast cancer patients had an impressive 81.8 percent response rate with 36.4 percent showing a complete response; and while metastatic TNBC patients had a 15.4 percent response rate, 53.8 percent received some clinical benefit (i.e., improvement in symptoms compared to patients receiving taxane alone).
In terms of determining how L-NMMA enhances chemotherapy, Dr. Chang and her colleagues homed in on the role of the tumor immune microenvironment in response to therapy. Previous studies showed that levels of specific immune cells were different in patients that responded to chemotherapy versus non-responders, particularly immune cells called neutrophils; and tumor-associated neutrophils were correlated with poor patient outcomes. Interestingly, neutrophils rely on iNOS, the target of L-NMMA.
Building on these studies, Dr. Chang examined the levels of 38 different immune cells and how they changed with L-NMMA plus chemotherapy treatment. Of note, researchers unexpectedly found that the levels of neutrophils were increased in patients that responded to the combination, and macrophages (another immune cell type) were increased in non-responders. Further studies are planned to unravel the mechanism behind the neutrophil and macrophage shifts in responders and non-responders, respectively.
In the future: Testing L-NMMA for the real world
These results support L-NMMA and chemotherapy as an effective treatment for locally advanced or metastatic TNBC. Dr. Chang and her team concluded that this combination warrants further investigation in larger phase 3 trials—potentially, bringing us a few steps closer to FDA approval of this strategy for patients with aggressive TNBC. This is welcome news and can give hope to these patients who have limited treatment options.
This step-by-step foundational research advances the field through clinical trials—ultimately improving outcomes for breast cancer patients. But unfortunately, researchers face a catch-22: While basic laboratory studies are critical, it’s difficult for investigators to secure funding for their work in the initial stages. That’s where BCRF comes in.
“Funding through BCRF and other philanthropic mechanisms enables the development of drugs through this stage where traditional funding sources are not available,” Dr. Chang said.
And BCRF support has ripple effects—like helping researchers obtain additional funding. For example, Dr. Chang and her team secured a large National Cancer Institute grant to conduct a phase 2 study that tests a novel therapeutic combination in metaplastic breast cancer—one of the most lethal types. Securing NCI funding indicates deep confidence in the potential and promise of this research, which would not have been possible without BCRF’s initial funding.
BCRF is proud to support early, fundamental science that fuels tomorrow’s progress in breast cancer treatment and gives researchers the time and flexibility to pursue their best ideas.
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