Abstract

The evaluation of candidate therapeutic agents for the treatment of bone marrow failure in patients with Fanconi anemia (FA) is constrained by several challenges including the disease heterogeneity and the limited number of primary human hematopoietic cells available to study. In vitro assays of human hematopoiesis do not provide information about the correction of long- term multilineage hematopoiesis, a critical endpoint that determines the efficacy of therapy for bone marrow failure in FA and related disorders. The predictive value of preclinical studies can be significantly enhanced by the use of robust in vivo modelling. We have developed a novel, double-chimeric xenograft model that allows us for the first time to rigorously test candidate therapeutic agents for their potential to correct steady-state human FA deficient hematopoiesis. The goal of this Xenograft Core is to fully evaluate the acute and chronic effects of the administration of lead therapeutic compounds identified in Projects 1 & 2 of this proposal.

Public Health Relevance

The goal of the Xenograft Core is to evaluate the efficacy of candidate therapeutic agents in Fanconi anemia. Lead compounds identified in Projects 1 & 2 of this proposal will be tested an in vivo model to determine their potential to enhance both short-term and long-term hematopoiesis in human Fanconi A deficiency.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048546-25
Application #
9983794
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Qasba, Pankaj
Project Start
Project End
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
25
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

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
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
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
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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