Triple-negative breast cancer (TNBC) — characterized by the lack of expression of estrogen receptor progesterone receptor,, and human epidermal glycation receptor 2 (HER2) — remains a challenge to treat as it has no clear biological target.
In the search for a target, a team of American researchers might have discovered a druggable spot that is the inducible nitric-oxide signaling (NOS) pathway.
In a phase 2 trial of 24 patients with chemo-resistant, locally advanced and metastatic TNBC, the use of a first-in-class pan-NOS inhibitor known as NG-monomethyl-l-arginine (L-NMMA) alongside docetaxel yielded an overall response rate of 45.8% (11 of 24 patients).
According to Jenny C. Chang (MD) who is the senior author of Houston Methodist Research Institute, Texas Medscape Medical News, the response rate was higher than the “usual expected” 25%-30 percent in this setting.
The results were published online on the 15th of December in Science Translational Medicine.
In the nonrandomized, nonblinded trial 24 patients were treated with L-NMMA at 20 mg/kg , along with taxane at the usual chemotherapy dose. Patients were treated for a maximum of six (21-day) cycles of the combination, with L-NMMA given as a 2-hour intravenous infusion on days 1 to 5 of each cycle.
Overall, 9 of 11 with locally advanced disease responded (81.8%) to treatment with four (36.4%) responding completely and five (45.5 percent) experiencing a partial response.
In the metastatic disease, 2 of 13 patients showed a response (15.4%) to treatment, and more than half (53.8 percent) had an improvement in their clinical condition, which combines rates for complete and partial responses as well as stable disease.
Chang and colleagues report that the findings in metastatic TNBC are noteworthy for patients who have had a median five chemotherapy regimens prior to the.
Additionally 21% of patients had toxicities of a grade greater than 3. However there were no adverse events caused by L-NMMA.
The antitumor activity is encouraging and impressive.
Charles Shapiro MD, from the Icahn school of medicine at Mount Sinai in New York City says that “the anti-tumor activities have been remarkable and encouraging.”
Shapiro who was not part of the trial and was not involved in the trial, said in Medscape Medical News that he believes the agent is now ready for the next phase of research, which will be a phase 2 study looking into the effectiveness of the drug in less heavily pretreated patients with TNBC.
Chang, the sole inventor of an application for patent protection for cancer treatment methods “using iNOS inhibitory compositions,” confirmed that the trial was the first to study the use of a NOS inhibitor in breast carcinoma.
In the past, L-NMMA was studied in the management of cardiogenic shock in the phase 3 trial and showed an “safe” toxic profile, the study’s authors said. However, the agent is associated with treatment-induced hypertension.
Patients in the trial received amlodipine for 6 days per cycle to prevent L-NMMA-induced Hypertension. Enteric-coated low-dose aspirin (81 mg) was administered orally once daily throughout as thromboembolic prophylaxis.
The authors suggest a possible mechanistic foundation to explain the oncologic reactions observed during the current trial.
“In our previous research, we discovered RPL39 and MLF2 genes that are associated with treatment resistance. The researchers explained that their bioinformatic analysis revealed that inducible NOS signaling was the main pathway that both genes share.
The findings also suggest a boost to the immune system of patients who responded to treatment. Researchers observed a trend in the number of CD4 T cells and CD8 T cells in patients who responded during cycle 1 (17 days). This was in contrast to those who did not respond. The trends remained consistent during cycle 2 (day 38) for CD8 T cell and monocyte numbers, however, there was no discernible distinction in CD4 T cells numbers between the two groups.
Responders had higher CD15+ neutrophil counts than nonresponders, and lower levels arginase, which is an indicator of tumor-supporting immune cell. Additionally, breast tissue samples from responders had a higher level of NOS at the beginning of treatment which decreased at the conclusion of treatment.
“We are actively investigating the phenotypic variations in immune cell populations in mouse models in preclinical and plan to confirm our results in a future phase 3 trial,” the team writes.
This study was funded by the National Cancer Institute, Breast Cancer Research Foundation, Moran Foundation, Causes for a Cure, M. Neal and R. Neal, and the Center for Drug Repositioning and Development Program. Some of the study authors have that they have financial ties to the industry. Chang is one of four authors who submitted a patent application to patent a method for predicting the response to treatment with LNMMA in breast cancer that is triple-negative.
Sci Transl Med. Published online on December 15th 2021. Abstract
Nick Mulcahy is an award-winning senior journalist for Medscape, focusing on oncology, and can be reached at [email protected] and on Twitter: @MulcahyNick
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