Oral cancer in Fanconi patients is a severe disease requiring innovative treatment and prevention measures. The potential use of FDA-approved diabetes drugs is a practical strategy for Fanconi patients for oral cancer prevention or treatment studies, once these preliminary studies are conducted.
There is an increased risk of oral cavity and other head and neck cancers as Fanconi patients live longer post transplantation. Fanconi patients also suffer from “field effect” in that treatment of the first oral cancer is frequently accompanied by recurrences and second primary malignancies which are fatal.
We seek safe and readily available drug agents to treat this vulnerable population. In the revised expanded preclinical study, we will investigate Actoplus Met components, Metformin/Pioglitazone, polo-like kinase 1 (PLK 1) inhibitor, GSK461364, and Wee1 kinase inhibitor, AZD1775, all agents of high interest in Fanconi anemia head and neck cancer treatment. Actoplus Met is a current agent under study in an NCI sponsored trial (clinicaltrials.gov NCT02917629). AZD1775 may act more effectively under states of p53 deficiency but also may synergize with other downregulators of mTOR making it particularly attractive for use with metformin (12-19). The PLK 1 inhibitor is also well tolerated and functions particularly well in p53 mutated cells (20,21). We will test the effects of these agents in Fanconi anemia cell lines in vitro, and mouse orthotopic and minimal residual disease models (22). The principal goal is identification of efficacious treatments and hypothesis driven biomarkers which can be rapidly translated to Fanconi patient clinical trials for prevention, precision medicine, or radiation/chemotherapy adjunctive therapy. This will be accomplished through the following two specific aims:
1) We will test pioglitazone, metformin, GSK461364, and AZD1775 on the growth and carcinogenic potential of Fanconi anemia cell lines in vitro
We hypothesize pioglitazone, metformin, GSK461364, and AZD1775 will inhibit growth and clonogenic potential in Fanconi cell lines (MOP FA1, VU 1131, VU 1365), and a reference oral squamous preneoplastic (MSK Leuk1), while using Lentivirus knockdown FANC A immortalized keratinocytes (or equivalent) in a coordinate safety study. Hypothesis driven markers will be tested via western blotting in treated and control cells for pharmacodynamic effects of the inhibitors.
2) We will test pioglitazone, metformin, GSK461364, and AZD1775 on growth and carcinogenic potential of Fanconi anemia cell lines in vivo
We hypothesize pioglitazone, metformin, GSK461364, and AZD1775, will inhibit growth of Fanconi anemia cells in both orthotopic and minimal residual disease models of oral cancer. Hypothesis driven markers will be tested by Western blotting in treated and control tumors for pharmacodynamic effects of the inhibitors. RNA-Seq experiments will be conducted with Ingenuity Pathway analysis to confirm Western blotting and identify on and off-target effects of the inhibitors.
Researchers: Frank G. Ondrey