Abstract

Fanconi Anemia (FA) is a devastating genetic disease characterized by progressive bone marrow failure, birth defects and cancer susceptibility. The clinical outcomes in terms of morbidity and mortality remain poor and the pharmacological therapy of FA has not changed in over 30 years. In the past funding period we identified multiple novel small molecules and therapeutic targets that have beneficial effects in FA models. In this project we will follow up on the following candidates: 1) metformin (Aim1), P38-MAPK inhibitors (Aim 2) and combinations of small molecules (Aim 3), including those from Aims 1 and 2 as well as Project 2. We will use murine models of FA and xenotransplants (Core B) to assess the effects of these regimens on human blood progenitors in vivo. Core C will perform DNA damage assays for our project and Project 3 will test our candidates on human FA cells in vitro. In aggregate these experiments will define the therapeutic potential of small molecule monotherapy or drug combinations for the treatment of bone marrow failure in FA.

Public Health Relevance

Successful completion of this project may result in a clinical trial of a novel small molecule or drug combination novel for Fanconi's Anemia. Furthermore, a treatment regimen that benefits bone marrow failure and delays leukemia in FA may well be useful in other forms of bone marrow failure.

  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 #
9983800
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
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

Showing the most recent 10 out of 106 publications