Head and neck cancer is one of the top five most common forms of malignancy. One of main problems in head and neck cancer treatment is local regional control and frequent recurrence. In this grant application, we propose to examine a hypothesis that may significantly improve the radiotherapy of H&N cancer. The long-term objective of this project is to characterize the status of the so-called "master switches": hypoxia-inducible factor (HIF) genes, during radiotherapy of head and neck cancer and to exploit such knowledge for potential therapeutic gain. The hypothesis of our project is that HIF-1&2 genes play key roles in determining head and neck (H&N) cancer responses to radiotherapy, and that inhibiting HIF-1&2 activities can enhance the efficacy of H&N cancer radiotherapy. Our project is based on previous studies indicating that hypoxia and both of the HIF-1&2 factors play important roles in determining prognosis of head and neck cancer radiotherapy. In addition, it is based on our new data that indicated HIF factors were activated by radiotherapy independent of hypoxia through the generation of intratumoral nitric oxide, which can stabilize the alpha subunits of the HIF genes. We will conduct experiments to systematically characterize radiation-induced HIF-1 and HIF-2 gene activation in preclinical head and neck cancer models by use of novel molecular imaging and transgenic mouse approaches. Specifically, we will examine the roles of specific nitric oxide synthase genes in radiation-induced HIF-1&2 activation (Specific aim 1). In addition, we will attempt to decipher the molecular mechanism through which nitric oxide mediates radiation-induced HIF-1&2 activation in head and neck cancer radiotherapy (Specific aim 2). Finally, we will evaluate the relative importance of these two factors in head and neck cancer survival after radiotherapy (Specific Aim 3). The proposed studies should provide important insights into the biological mechanisms of radiation-induced activation of the HIF genes and evaluate the efficacy for inhibiting these two factors during head and neck cancer radiotherapy.

Public Health Relevance

This project studies the mechanism of the involvement of the HIF genes in radiotherapy treatment of head and neck cancer. It may provide new insights that allow for the development of new therapeutics that can enhance current head and neck cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA131408-04
Application #
8205026
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2009-03-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$316,002
Indirect Cost
$114,727
Name
Duke University
Department
Dermatology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Donato, Anne L; Huang, Qian; Liu, Xinjian et al. (2014) Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy. J Invest Dermatol 134:1686-92
Liu, XinJian; Huang, Qian; Li, Fang et al. (2014) Enhancing the efficiency of direct reprogramming of human primary fibroblasts into dopaminergic neuron-like cells through p53 suppression. Sci China Life Sci 57:867-75
Ma, Jingjing; Tian, Ling; Cheng, Jin et al. (2013) Sonic hedgehog signaling pathway supports cancer cell growth during cancer radiotherapy. PLoS One 8:e65032
Zimmerman, Mary A; Huang, Qian; Li, Fang et al. (2013) Cell death-stimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy. Semin Radiat Oncol 23:288-95
Brogan, John; Li, Fang; Li, Wenrong et al. (2012) Imaging molecular pathways: reporter genes. Radiat Res 177:508-13
Liu, Xinjian; Li, Fang; Stubblefield, Elizabeth A et al. (2012) Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 22:321-32
Li, Wenrong; Li, Fang; Huang, Qian et al. (2011) Quantitative, noninvasive imaging of radiation-induced DNA double-strand breaks in vivo. Cancer Res 71:4130-7
Huang, Qian; Li, Fang; Liu, Xinjian et al. (2011) Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med 17:860-6
Wolf, Frank; Li, Wenrong; Li, Fang et al. (2011) Novel luciferase-based reporter system to monitor activation of ErbB2/Her2/neu pathway noninvasively during radiotherapy. Int J Radiat Oncol Biol Phys 79:233-8
Li, Fang; Huang, Qian; Chen, Jiang et al. (2010) Apoptotic cells activate the "phoenix rising" pathway to promote wound healing and tissue regeneration. Sci Signal 3:ra13

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