Abstract 658: Antiproliferative effects of type II diabetes agents in Fanconi derived oral squamous carcinoma

Abstract

Abstract Fanconi anemia is a rare disease characterized by bone marrow failure requiring transplantation at a young age. Patients with Fanconi Anemia are at risk for the development of squamous cell carcinomas of the skin and mucosal surfaces at risks several hundred fold higher than control populations and these malignancies can pursue an aggressive, often fatal, course. Our group has been interested in repurposing Type 2 diabetes agents for oral cancer prevention and treatment. Presently, we examined the effects of the thiazolidinedione drug, pioglitazone, and an experimental biguanide, N1-hexyl-N5-benzyl-biguanide (HBB), on the proliferation of Fanconi-derived oral carcinoma cells. We incubated MOP FA1,a, VU-1131, and VU-1365 b, and C squamous cell carcinoma cell lines with vehicle controls or the thiazolidinedione pioglitazone or biguanide (HBB). We found dose-dependent decreases in cellular proliferation in all three Fanconi-derived cell lines at physiologically relevant concentrations (10 - 50 µM) after 1 to 3 days in several experiments. The effects were not due to simple cytotoxicity as judged by trypan blue staining. In other non-squamous cell lines of cervical and oral cavity origins we have previously discovered similar effects. These agents affect PPAR gamma associated pathways (pioglitazone) or mTOR and mitochondrial glucose metaboliscm pathways (HBB). Since Fanconi anemia patients are highly susceptible to DNA damaging effects of cytotoxic chemotherapy, these classes of agents might be attractive in Fanconi Anemia oral cancer treatment or prevention. Metformin, another biguanide, is currently postulated to delay bone marrow failure in the Fanconi population and is currently in use in an early phase clinical trial. Our results may, therefore, be attratciveattractive for oral cancer prevention and treatment in this population, as they are well tolerated. Further examination of molecular mechanisms will likely generate putative pharmacodynamics markers for future clinical trials. Citation Format: Kim Miller, Beverly Wuertz, David Potter, Frank G. Ondrey. Antiproliferative effects of type II diabetes agents in Fanconi derived oral squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 658.