Abstract LB-211: Synergistic anti-metastatic effect of pembrolizumab in combination with a novel mTORC1 inhibitor/AMPK agonist in a CAM metastatic triple negative breast cancer model

Abstract

Abstract Triple negative breast cancer (TNBC) is highly aggressive and has higher rates of recurrence, resistance, and death than other breast cancers. Ten year survival rate is < 50%. Changes in the tumor stroma create an environment that provides support for tumor growth, progression, invasion and metastasis. The most prominent cell type in the tumor stroma is an activated form of fibroblasts, known as cancer associated fibroblasts (CAFs). In breast cancer, as much as 80% of stromal fibroblasts acquire the CAF phenotype secreting growth factors, hormones, and cytokines that act upon both the tumor and the stroma to promote the metastatic phenotype. NovoMedix has developed a novel mTORC1 inhibitor/AMPK agonist (NMIC9) that inhibits tumor cell proliferation, migration (98% decrease, p=0.0002), and invasion; and it prevents activation of the tumor stroma and formation of CAFs. NMIC9, a small molecule, has demonstrated oral efficacy as a single agent in mouse models of TNBC (93% reduction in tumor growth, p<0.005, with no significant tumor regrowth after treatment cessation) and safety in non-GLP toxicology studies in rats (NOAEL > 1000 mg/kg p.o.). Further, NMIC9 has no hERG effects, no CYP interactions, no mutagenicity in the AMES assay, and no kinase inhibition. Many TNBC therapies cause cardiomyopathy leading to heart failure. In primary mouse adult ventricular cardiomyocytes, addition of NMIC9 significantly reduces DOX-induced cardiomyocyte apoptosis and death (p<0.001) while increasing efficacy in TNBC cells. Further, daily treatment with NMIC9 at therapeutic levels for 8 weeks did not cause any changes in cardiac structure or function, indicating that there are no cardiac liabilities. Inhibition of metastases is particularly relevant for TNBC because it is the main cause of mortality. While immune checkpoint inhibitors have shown remarkable response rates in several types of cancer, the response rate in TNBC is only 5 – 30%. A drug that could increase efficacy of immune checkpoint inhibitors and decrease metastasis in TNBC could dramatically improve outcomes for these patients. Recent data in a chicken chorioallantoic membrane model with a highly aggressive TNBC cell line (MDA-MB-231) show that NMIC9 decreases tumor growth and metastasis alone and in combination with pembrolizumab. Tumor regression was 20% for pembrolizumab (ns), 30% for NMIC9 (p<0.05), and 64% for pembrolizumab + NMIC9 (p<0.005). Decrease in metastasis invasion was -0.08% (ns) for pembrolizumab, 49% (p<0.05) for NMIC9, and 64% (p<0.005) for pembrolizumab + NMIC9. Therefore, NMIC9 is a promising first in class drug, which when used in combination with pembrolizumab can significantly reduce tumor growth and metastasis and improve survival rates in TNBC. Citation Format: Leah Fung, Laura G. Corral, Robert W. Sullivan, Kyle W. Chan, Cathy A. Swindlehurst. Synergistic anti-metastatic effect of pembrolizumab in combination with a novel mTORC1 inhibitor/AMPK agonist in a CAM metastatic triple negative breast cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-211.