On September 25, 2020 Nirogy Therapeutics Inc. reported that it was awarded a $2M NIH/NCI SBIR grant to develop dual monocarboxylate transport inhibitors (dMCTi) for Triple Negative Breast Cancer (TNBC) (Press release, Nirogy Therapeutics, SEP 25, 2020, View Source [SID1234576776]).
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"We are delighted to receive this highly competitive award from NIH/NCI under small business innovation research grant program. We are appreciative of the continued support from NCI for our breast cancer program. I believe that this award attests the validity of our science strategy to target the untapped class of solute carrier transporters (SLCT) family of proteins for cancer, and the progress we have made so far in this breast cancer program. This fund allows us to rapidly move through the initial stages of commercialization activities and execute part of the IND enabling studies for the pre-clinical development candidate compound" stated Dr. Vincent Sandanayaka, Founder, President & CEO of Nirogy Therapeutics.
Worldwide, approximately 1 million women are diagnosed with breast cancer each year. TNBC is the deadliest sub-type of breast cancer, accounting for ~15% of the breast cancer diagnoses and ~25% of breast cancer-related deaths. Median survival for 30% of the patients with TNBC is just one year. TNBC has poor clinical outcomes due to its high metastatic rate, resistance to chemotherapy, and lack of effective treatment options. The lactate-rich tumor microenvironment (TME) of TNBC has been shown to be highly immunosuppressive, promoting tumor growth and progression. Lactate metabolite produced from glucose metabolism via glycolysis is increasingly recognized as a strong immune suppressor in many tumors.
Cancer cells transport lactate across the cell membrane to the extracellular matrix via monocarboxylate transporters, MCT1 and MCT4. We have discovered that dMCTi block lactate excretion to the TME, thereby directly killing cancer cells and simultaneously activating local immunity in the TME. In our preliminary studies, we have shown that dMCTi are potent compounds against multiple TNBC cell lines. Also, we have shown that in both mouse xenograft models (MDA-MB-231, TNBC), and syngeneic mouse models (SM1, BRAFV600E, melanoma; and 4T1, TNBC), dMCTi exert significant anti-tumor efficacy. In 4T1 and SM1 syngeneic models, we observed a decrease in expression of multiple immunosuppressive molecules such as B7H family proteins, M2 macrophages, and MDSCs while increase in CD8+ population in treated tumors compared to the control tumors. Furthermore, the profiling of cytokines in these tumors indicated an increase in pro-inflammatory IFNγ, TNFα, IL-1β and decrease in tumor promoting TGFβ, IL-10 compared to the control tumors, confirming that the anti-tumor effect of dMCTi is in part due to the enhanced immune function.