Due to significant improvements in the early detection and the treatment of cancer, the number of cancer survivors is increasing. Unfortunately, long-term cancer survivors are at increased risk for late effects related to cancer treatment, including ionizing radiation (IR)- and chemotherapy-induced long-term bone marrow (LT-BM) injury. LT-BM injury is primarily attributed to selective induction of oxidative stress and senescence in hematopoietic stem cells (HSCs). The goals of this project are to use our well characterized LT-BM injury mouse models induced by total body irradiation (TBI) or chemotherapy to (1) identify the primary cellular origins of reactive oxygen species (ROS) in HSCs, (2) elucidate how production of ROS in HSCs is regulated, and (3) develop a mechanism-based strategy that can effectively inhibit IR- and chemotherapy-induced HSC senescence and LT-BM suppression via selective inhibition of ROS production in HSCs. Specifically, the hypotheses to be tested are that (1) ROS derived from NADPH oxidase 4 (NOX4) is primarily responsible for mediating IR- and chemotherapy-induced HSC senescence and (2) inhibition of NOX4 can be developed as a novel therapeutic strategy to effectively reduce IR- and chemotherapy-induced LT-BM injury.
Three specific aims will be pursued to test these hypotheses.
Aim 1 : Determine whether NOX4 is primarily responsible for the production of ROS in HSCs to mediate TBI-induced HSC senescence and LT-BM injury.
Aim 2 : Investigate whether activation of the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1 (HIF1) pathway mediates IR-induced upregulation of NOX4 in HSCs.
Aim 3 : Determine whether inhibition of NOX4 activity with a NOX inhibitor or suppression of NOX4 upregulation with an mTOR inhibitor can effectively inhibit HSC senescence and LT-BM injury induced by not only IR but also chemotherapy. These proposed studies will gain fundamental insights into the pathogenesis of LT-BM injury induced by IR and chemotherapy. These insights will aid in the development of more effective strategies to prevent and mitigate IR- and chemotherapy-induced LT-BM toxicity. Because increased expression of NOX4 and aberrant activation of mTOR are involved in tumorigenesis and tumor resistance to therapy, targeted inhibition of NOX4 or mTOR may provide cancer patients the dual benefits of reducing IR- and chemotherapy-induced LT-BM suppression while increasing tumor response to cancer therapy.

Public Health Relevance

This project focuses on elucidating the fundamental molecular mechanisms by which ionizing radiation (IR) and chemotherapy induce long-term bone marrow (LT-BM) injury. The results of the proposed studies can lead to the development of more effective strategies to prevent and mitigate IR- and chemotherapy-induced LT-BM toxicity in cancer patients. Such strategies can significantly reduce the potentially life-threatening long-term effects of conventional cancer therapy on the hematopoietic system, increase the compliance of cancer patients to subsequent consolidation cancer treatments, and facilitate the long-term engraftment and recovery of hematopoietic function after autologous and allogeneic BM transplantation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA122023-06
Application #
8725832
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2006-07-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$274,607
Indirect Cost
$90,307
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Wang, Yingying; Boerma, Marjan; Zhou, Daohong (2016) Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases. Radiat Res 186:153-61
Chang, Jianhui; Wang, Yingying; Shao, Lijian et al. (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22:78-83
Demaria, Marco; O'Leary, Monique N; Chang, Jianhui et al. (2016) Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov :
Liu, Y Lucy; Yan, Yan; Webster, Cody et al. (2016) Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy. Blood 127:1912-22
Wang, Yingying; Chang, Jianhui; Shao, Lijian et al. (2016) Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks. Radiat Res 185:630-7
Wu, Yuehan; Lee, Suk-Hee; Williamson, Elizabeth A et al. (2015) EEPD1 Rescues Stressed Replication Forks and Maintains Genome Stability by Promoting End Resection and Homologous Recombination Repair. PLoS Genet 11:e1005675
Li, Chengcheng; Lu, Lu; Zhang, Junling et al. (2015) Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation. Cell Biosci 5:65
Pathak, Rupak; Shao, Lijian; Ghosh, Sanchita P et al. (2015) Thrombomodulin contributes to gamma tocotrienol-mediated lethality protection and hematopoietic cell recovery in irradiated mice. PLoS One 10:e0122511
Xu, Guoshun; Wu, Hongying; Zhang, Junling et al. (2015) Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic Biol Med 87:15-25
Zhou, Daohong; Shao, Lijian; Spitz, Douglas R (2014) Reactive oxygen species in normal and tumor stem cells. Adv Cancer Res 122:1-67

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