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.
|Whiteaker, Jeffrey R; Zhao, Lei; Ivey, Richard G et al. (2018) Targeted mass spectrometry enables robust quantification of FANCD2 mono-ubiquitination in response to DNA damage. DNA Repair (Amst) 65:47-53|
|Kroeger Jr, Paul T; Drummond, Bridgette E; Miceli, Rachel et al. (2017) The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. Dev Biol 428:148-163|
|Rondinelli, Beatrice; Gogola, Ewa; Yücel, Hatice et al. (2017) EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol 19:1371-1378|
|Karras, Georgios I; Yi, Song; Sahni, Nidhi et al. (2017) HSP90 Shapes the Consequences of Human Genetic Variation. Cell 168:856-866.e12|
|Mouw, Kent W; Goldberg, Michael S; Konstantinopoulos, Panagiotis A et al. (2017) DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer Discov 7:675-693|
|Garbati, Michael R; Hays, Laura E; Rathbun, R Keaney et al. (2016) Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages. J Leukoc Biol 99:455-65|
|Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew et al. (2016) Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. Blood 128:2774-2784|
|Zhang, Haojian; Kozono, David E; O'Connor, Kevin W et al. (2016) TGF-? Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia. Cell Stem Cell 18:668-81|
|Zhang, Qing-Shuo; Benedetti, Eric; Deater, Matthew et al. (2015) Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Reports 4:90-102|
|Lombardi, Anne J; Hoskins, Elizabeth E; Foglesong, Grant D et al. (2015) Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers. Clin Cancer Res 21:1962-72|
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