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Potential chemopreventive treatments in Fanconi anemia related oral squamous carcinoma
Poster Title: Potential chemopreventive treatments in Fanconi anemia related oral squamous carcinoma
Submitted on 28 Oct 2022
Author(s): Kimberly A Miller, Beverly R Wuertz, Anna Haynes, David A Potter, and Frank G Ondrey
Affiliations: Molecular Oncology Program, Departments of Otolaryngology & Medicine, University of Minnesota, Minneapolis, MN
This poster was presented at AACR 2018
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Poster Information
Abstract: Fanconi anemia (FA) is a DNA repair mechanism genetic disorder which leads to bone marrow failure and cancer. Risk of solid tumor malignancy in FA patients occurs decades earlier and at a rate several hundred-fold higher than the general population, necessitating regular cancer surveillance. Development of an adjunct therapy or preventative survival-enhancing therapy with a minimal side effect profile will benefit this population in which chemotherapy and radiation are particularly damaging.
To this end, we established a cell line from a post bone marrow transplant FA patient with a T2N2bM0 oral SCC grown as an adherent monolayer culture. We tested pioglitazone, metformin, and N1-hexyl-N5-benzyl-biguanide (HBB), emerging chemopreventative therapies for head and neck squamous carcinoma, for growth inhibition in head and neck cancer cell lines, including our FA SCC cell line. Additional cell lines include UMSCC 11A (laryngeal squamous cell carcinoma), CA 9-22 (oral squamous cell carcinoma), Beas2B (SV40 immortalized normal bronchial epithelium), and MSK Leuk1 (oral leukoplakia cell line). All cell lines are HPV negative. MTT assays determined cell viability after 1, 2, and 3 days of treatment. Pioglitazone at all concentrations (5, 10, 20, 40 μM) decreases cell proliferation compared to solvent controls (P<0.0001). Metformin (1 μM – 1 mM) unexpectedly increased cell proliferation or was otherwise equal in growth with the controls, and at higher doses (10 mM – 100 mM) metformin decreased cell proliferation or resulted in cytotoxicity (P<0.0001). Pioglitazone (10 μM) and metformin (above 1 mM) resulted in larger, cell line dependent, decreases in cell proliferation than either agent alone. In the FA cell line, pioglitazone and HBB resulted in increased efficacy. HBB treatment resulted in decreases in proliferation and percent live cells at 20 μM equivalent to the effect of 10 to 100 mM metformin. Combining HBB with 10 μM pioglitazone decreased cell proliferation and percent live cells over pioglitazone alone. HBB also caused S phase blockade in a pilot FA cell cycle experiment. Pioglitazone combined with HBB appears to be a promising chemopreventative adjunct treatment for HNSCC in FA patients. Further studies are underway to evaluate the relative contribution of HBB to decreased cell proliferation versus apoptotic mechanisms. Recent studies of HBB in breast cancer indicate cytochrome P450 arachidonic acid epoxygenase activity as an HBB target and suggest further exploration of this target in head and neck squamous cell carcinoma.
Summary: Poster summarizes preliminary data combining HBB, a novel metformin equivalent with Pioglitazone, another Type 2 Diabetes drug for possible application in chemoprevention.References: See within posterReport abuse »
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