Long‐term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model

Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number inFancd2−/−mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts ofFancd2−/−mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3weeks to 18months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=.01) and hemoglobin levels (p<.05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin−Sca+c‐Kit+]) was significantly increased (p=.001) by long‐term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused byFancd2deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long‐term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. Liver samples were collected from sex-matched (male) mice after 18 months of treatment. RNA was isolated and cDNA libraries constructed from five groups: wildtype untreated, Fancd2 mutant untreated, Fancd2 mutant metformin-treated, fancd2 mutant oxymetholone-treated, and fancd2 mutant metformin+oxymetholone treated