Abstract IA10: Fanconi anemia and novel drug targets
Authors: D'Andrea Alan D. 
Published: May 2015

Abstract
The fifteen Fanconi Anemia proteins cooperate in a novel DNA repair pathway, required for DNA interstrand crosslink repair during S phase of the human cell cycle. Disruption of this pathway results in congenital abnormalities, bone marrow failure, and cancer susceptibility, most notably Acute Myeloblastic Leukemia and Squamous Cell Carcinomas. A molecular understanding of the FA pathway has emerged over the last several years, and insights from this pathway have suggested novel drug targets and therapeutic strategies for FA patients. In my talk, I will discuss three research areas that may result in new drug strategies.
First, the FA pathway plays a critical role in the regulation of Cytokinesis (i.e., the orderly condensation and separation of sister chromatids during the mitosis phase of the cell cycle). Recent studies indicate that some FA proteins, including FANCD2, FANCI, and FANCM, as well as the BLM helicase, accumulate at ultrafine bridges connecting sister chromatids in mitosis. Interestingly, defects in the FA pathway cause an increase in these bridges, thereby resulting in cytokinesis failure and an increase in binucleate cells. These FA cells appear to undergo rapid p53-mediated apoptosis, perhaps contributing to the bone marrow failure observed in FA mouse models and FA patients. Pharmacologic blockade of this apoptotic cell death may result in the rescue of bone marrow hematopoietic progenitor cells and in an enhancement of hematopoiesis.
Second, downstream FA proteins (ie, FA proteins which are not required for FANCD2 monoubiquitination), such as FANCD1/BRCA2, are directly involved in homologous recombination (HR). Loss of these proteins can result in a decrease in the assembly of RAD51-mediated nucleofilaments (i.e. structures essential for HR). We have recently identified an anti-recombinase protein, called PARI (PCNA-Associated Recombination Inhibitor). Interestingly, downregulation of PARI results in an enhancement of HR in FA pathway deficient cells and a rescue of DNA crosslinker-induced chromosome radial formation. Thus, pharmacologic blockade of PARI may provide a novel strategy for promoting HR in the bone marrow cells for some FA pathway deficient patients.
Third, recent studies indicate that the FA pathway provides an important tumor suppressor activity, which is especially critical in epithelial cells. Epithelial cells which are deficient in FANCD2-Ub undergo have increased cellular proliferation and decreased senescence. This function of FANCD2-Ub in epithelial cells may account, at least in part for the predisposition of FA patients to Squamous Cell Carcinomas (SCCs). Knockdown or inhibition of the deubiquitinating enzyme, USP1, results in increased FANCD2-Ub levels and an increase in FANCD2-Ub levels in some FA mouse models and in FA patient-derived cell lines. Accordingly, a USP1 inhibitor may provide a novel strategy for SCC chemoprevention for some FA patients. To summarize, the overall goal of our research program is to identify pathway-based treatment strategies for FA.
Citation Format: Alan D. D'Andrea. Fanconi anemia and novel drug targets. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA10.