Concomitant chemo/radiotherapy has improved the cure rates in many malignant neoplasms. This approach is limited by both systemic toxicity and adapted resistance. One solution is selective targeting at tumors with complimentary mechanisms, such as spatially and temporally controlled radiation, tumor-specific drug delivery, and blockades for tumor survival pathways. Our long term goal is to elucidate mechanisms of tumor response to radiation, and explore the mechanisms to improve therapeutic efficacy and decrease systemic toxicity of cancer radiotherapy. We isolated one short peptide that specifically binds to radiation-treated tumor microvasculature, the peptide sensitized tumor response to radiation in vitro and in vivo. We found that Tax- interacting protein 1 (TIP-1) is responsible for the peptide's specific binding within the irradiated tumor, radiation induces de novo synthesis and translocation of TIP-1 to cell membrane. This application is to study the biological roles of TIP-1 in tumor response to radiation, and utilize the tumor-selective peptide for tumor- targeted drug delivery. The significance of the proposed research is in studying a novel phenomenon of radiation-inducible expression and translocation of TIP-1 within tumor. Utilizing a peptide that selectively binds and sensitizes tumor to radiotherapy for tumor-targeted drug delivery will not only enhance efficacy of cancer radiotherapy by combining modalities of complementary mechanisms (radiation, inhibitory antibody or peptide, and delivered drug), but also reduce systemic toxicity by limiting cytocixity only within tumors since expression of the novel protein is strictly regulated by spatially and temporally controlled radiation.

Public Health Relevance

We discovered radiation induces de novo synthesis and membrane translocation of TIP-1, which may mediate cytotoxic effect of one tumor-selective peptide on irradiated tumors. This application is to study biological roles of TIP-1 in tumor response to radiation, and utilize the tumor-selective peptide for tumor- targeted drug delivery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127482-04
Application #
8050171
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2008-06-02
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2011
Total Cost
$278,062
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang et al. (2013) Expression of Tax-interacting protein 1 (TIP-1) facilitates angiogenesis and tumor formation of human glioblastoma cells in nude mice. Cancer Lett 328:55-64
Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang et al. (2012) Expression of TIP-1 confers radioresistance of malignant glioma cells. PLoS One 7:e45402
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Wang, Hailun; Yan, Heping; Fu, Allie et al. (2010) TIP-1 translocation onto the cell plasma membrane is a molecular biomarker of tumor response to ionizing radiation. PLoS One 5:e12051