February 2025
Published: 05 Feb 2025
Author: Precedence Research
Houston Methodist researchers have discovered a drug combo with the potential to revolutionize treatment for metaplastic breast cancer (MpBC), a rare and highly aggressive form of breast cancer. Any standard-line chemotherapy used for MpBC is sometimes resistant, while about 50% of MpBC cases come back after the first line of therapy, meaning there are few effective treatments left. MpBC is treated in basically the same manner as triple-negative breast cancer (TNBC), with chemotherapy followed by surgery and radiation. Unfortunately, such therapies have proven largely ineffective in staving off recurrence or metastasis.
The study indicated that high NOS2 expression levels correlate with poor MFS outcomes. The researchers proposed that concomitant targeting of both pathways, NOS and PI3K, should provide better outcomes for MpBC patients. With this in mind, they tested this hypothesis in vitro using a combination of two inhibitors: alpelisib-an already established PI3K inhibitor for the treatment of advanced cancers-and L-NMMA-an NOS inhibitor that is usually applied in such conditions as septic shock and cardiovascular diseases. This combination effectively blocked signaling pathways that promote MPBC tumor growth, thus attenuating cancer aggressiveness and enhancing tumor response.
Dr. Jenny Chang, MD, CEO of the Houston Methodist Academic Institute, stated that the drug combination for aggressive breast cancer shows promise in bettering patient outcomes for those with limited options and poor prognosis. The combination was evaluated in a phase Ib/II preclinical trial for drug effectiveness in patients with chemorefractory locally advanced breast cancer (LABC) or metastatic TNBC.
Results were encouraging for additional preclinical discussions, including increased tumor differentiation, decreased cancer stem cell markers, and prolonged metastasis-free survival. The drug combination affected two very important signaling pathways: the PI3K Pathway and NOS Pathway in tumor progression and inflammation. By interrupting both signaling pathways, this drug combination conspicuously diminished the survival mechanisms of MpBC cells and thereby made them more susceptible to the treatment. Hence, the present research is a step forward in cancer research and therapy.
The study of tumor biopsy samples for MpBC has yielded promising results but does have limitations. The small sample size requires larger clinical trials. Due to the rarity of the MpBC, scientific studies for this condition are grossly underrepresented, and larger studies would need to help understand the molecular features. The long-term combined effects of the two FDA-approved drugs on MpBC patients need to be investigated. The research team has initiated an NCI-funded clinical trial to fine-tune and validate the already developed therapeutic strategy, which may impact the treatment of other cancers targeting the PI3K and NOS pathways.
According to Dr. Tejaswini Reddy, a resident physician at Baylor College of Medicine, a combination treatment with an emphasis on the PI3K and NOS pathways will be studied. This research could change treatment paradigms for metaplastic breast cancer, an extremely rare and aggressive disease. If the transition occurs from research to a National Cancer Institute-supported clinical trial, this would, in turn, affect patient outcomes. Targeted therapies have provided renewed hope for MpBC patients, and with further investigations and clinical trials, this finding could change treatment approaches and ultimately improve survival rates. Therefore, the future of MpBC treatment is a bright one in terms of enhancing patient outcomes and quality of life.
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