Fanconi's Anemia (FA) is a genetic bone marrow failure syndrome that presents in childhood. Congenital malformations and increased cancer risk, particularly acute myelogenous leukemia, are additional manifestations of the disorder. Eighteen distinct genes responsible for the FA phenotype have been identified and together constitute the FA/BRCA network which functions to maintain genome stability and ensure stem cell survival. FA is associated with significant morbidity and early mortality and therapeutic options remain suboptimal. In the past funding period this Program Project succeeded in discovering new drug targets and small molecules for FA therapy. All of these candidates have clinical potential and we are on the threshold of new interventions for this severe disease. The key goal of the project in the next funding period is to prioritize a single drug regimen from our small list of candidates and to generate the preclinical data needed for starting a clinical trial. This Program Project will use a multidisciplinary approach to achieve this goal. The clinical disciplines represented include pediatrics, hematology, oncology and medical genetics. The scientific areas of expertise include molecular hematology, xenotransplantation, DNA repair, cell biology and mouse genetics. Project 1 will explore compounds that have already shown promise in FA mouse models such as metformin, p38 MAPK inhibitors, antioxidants and androgens, both singly and in combination. Project 2 will focus on inhibitors of the TGF-? pathway for the treatment of FA. Project 3 will use primary human cells from FA patients to study the compounds from projects 1 and 2. In addition, the regulatory groundwork for a clinical trial will be done. Core B will evaluate compounds in xenotransplant models of human hematopoiesis. Core C will perform a variety of DNA damage assays in support of all projects. Core D is a biorepository and Core A will provide administrative support.
The significance of this Program Project is very straightforward: Successful completion of our work will result in a clinical trial of a novel small molecule monotherapy or drug combination for Fanconi's Anemia. Furthermore, a treatment regiment that benefits bone marrow failure and delays cancer in FA may well be useful in other forms of aplastic anemia.
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