Human cancers develop in a complex environment composed of blood vessels, fibroblasts, and immune cells. The tumor microenvironment contributes to cancer development, progression, and response to therapy. Nearly two-thirds of all cancer patients receive radiation therapy during their illness. Although greater than 75% of these patients are treated with the intent to cure, it remains unclear if radiation cures tumors by killing tumor parenchymal cells or supporting stromal cells such as endothelial cells. The long-term goal of this study is to determine the mechanisms of tumor cure by radiation to enhance the efficacy of radiation therapy in the clinic. The overall objective of this application is to deine the cellular target(s) of radiation therapy in primary mouse models of cancer. Utilizing the two highly efficient site-specific recombinases, Cre and Flp, it is possible to contemporaneously mutate different genes specifically in tumor parenchymal cells and stromal cells. This dual recombinase technology enables the radiosensitivity of either the tumor parenchyma or the tumor microenvironment to be manipulated in primary tumors by mutating genes involved in DNA damage repair and apoptosis. The central hypothesis of this study is that radiation therapy cures tumors by killing tumor parenchymal cells rather than endothelial cells. Using micro-CT targeted irradiation and genetically engineered mouse models of primary lung adenocarcinoma and soft tissue sarcoma, the following specific aims will be completed:
Aim 1 : Determine the contribution of endothelial cells to tumor response to radiotherapy.
Aim 2 : Determine the contribution of tumor parenchymal cells to tumor response to radiotherapy. By selectively sensitizing or protecting either tumor parenchymal cells or endothelial cells, the critical target() of radiation therapy in primary cancers will be defined. Evaluating the contribution of the tumor microenvironment to tumor response to radiation therapy will help determine the viability of targeting stromal cells to improve the efficacy of radiation therapy in the clinic.

Public Health Relevance

The proposed research is relevant to public health because nearly two-thirds of all cancer patients receive radiation therapy, but the contribution of supporting stromal cells to tumor cure by radiation therapy remains unclear. Thus, the proposed research is relevant to the NCI's mission because it may lead to innovative approaches that enhance the efficacy of cancer therapy.

Agency
National Institute of Health (NIH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA177220-02
Application #
8641563
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Ashton, Jeffrey R; Clark, Darin P; Moding, Everett J et al. (2014) Dual-energy micro-CT functional imaging of primary lung cancer in mice using gold and iodine nanoparticle contrast agents: a validation study. PLoS One 9:e88129
Moding, Everett J; Lee, Chang-Lung; Castle, Katherine D et al. (2014) Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J Clin Invest 124:3325-38