Abstract 914: Pioglitazone and metformin as potential chemopreventative treatments in Fanconi anemia related oral squamous carcinoma

Abstract

Abstract Fanconi anemia (FA) is a genetic disorder which leads to bone marrow failure and cancer due to mutations in DNA repair mechanisms. FA is also a solid tumor-prone disease, affecting patients decades earlier and at a rate several hundred-fold higher than the general population necessitating regular cancer surveillance. To better understand the features of post-BMT oral SCC tumors and assist in development of preventative, survival-enhancing therapies for FA patients, we established a cell line and treated it with a panel of emerging chemopreventatives and natural compounds. An adjunct therapy with a minimal side effect profile will help this population in which chemotherapy and radiation are particularly damaging. We established a cell line from a post bone marrow transplant FA patient with a T2N2bM0 oral SCC grown as an adherent monolayer culture. The chemopreventative compound panel we used included Pioglitazone and Metformin. We also tested the synthetic retinoid Bexarotene, and commonly used chemotherapeutics Taxol and Cisplatin. MTT assays determined cell viability after 1, 2, and 3 days of treatment. Clonogenic assays were performed to determine survival and proliferation over 1-2 weeks. Reporter gene assays were performed to determine the effect of treatments on several target genes, to investigate pathway response and potential candidate biomarkers. Our results show Pioglitazone at all concentrations (5, 10, 20, 40μM) decreases cell proliferation compared to solvent controls (P<0.0001). Metformin (1 - 100μM) unexpectedly increased cell proliferation or was otherwise equal in growth with the controls, with the exception of the high dose (10mM) which decreased cell proliferation (P<0.0001). Taxol, Cisplatin, and Bexarotene were also found to decrease cell proliferation in a dose-dependent manner. Clonogenic assays demonstrated dose-dependent decreases in colony forming ability with Pioglitazone and Bexarotene, however no significant changes were shown with Metformin treatments. Reporter gene assays revealed that PPAR ligand binding activity was upregulated in FA cells treated with Pioglitazone (P<0.02 at 40μM, P = 0.0003 at 10μM) compared to controls. Conversely PPAR activity was decreased compared to controls in FA cells treated with Metformin (P<0.0001 for all concentrations of Metformin) and Bexarotene (P<0.0001 for all concentrations of Bexarotene 1, 2, 4μM). Pioglitazone seems to be a promising chemopreventative adjunct treatment for HNSCC in FA patients. Further studies are underway to evaluate the contribution of decreased cell proliferation versus apoptotic mechanisms. Metformin does not appear to decrease tumor cell proliferation at doses up to 100 uM in our FA cell line. Citation Format: Kim Miller, Beverly Wuertz, Frank G. Ondrey. Pioglitazone and metformin as potential chemopreventative treatments in Fanconi anemia related oral squamous carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 914. doi:10.1158/1538-7445.AM2015-914