Fanconi Anemia: Emerging Therapeutic Opportunities

Abstract SCI-1

Fanconi anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure, birth defects, and cancer susceptibility. At the cellular level, FA features hypersensitivity to DNA cross-linking agents, cell cycle abnormalities, and abnormal responses to cytokines. Therapy for the hematopoietic defects of FA has consisted of supportive care, stem cell transplantation, and administration of androgens such as oxymetholone. Unfortunately, even successfully transplanted FA patients have a very high risk of subsequent solid tumors, especially squamous cell carcinomas of the oropharyngeal and urogenital areas. The pharmacologic treatment of FA has been unchanged for several decades, and for this reason our group has embarked on a systematic search for small-molecule therapeutics that could benefit FA patients. This effort has been made possible by the cloning of 15 FA genes and biochemical insights into the function of FA proteins. Mouse models, zebra fish models, and FA patient cell lines, including induced pluripotent stem cells, are available for screening and validation. The specific goals of small-molecule interventions are to delay or prevent hematopoietic failure and also to delay or prevent carcinogenesis. To date, we have shown that the superoxide dismutase mimetic drug Tempol can significantly delay tumor formation in FA mice. Similarly, resveratrol clearly improved hematopoiesis in the same model. Medium-throughput screens have revealed numerous new molecules that ameliorate the FA phenotypes of cells, mice, and zebrafish. Using genetic approaches we also have identified the p53 pathway as a therapeutic target in FA. These therapeutic opportunities and progress in FA small-molecule screening will be discussed.