Radiotherapy remains a mainstay in cancer treatment yet many patients obtain no benefit in disease-free survival. The microenvironment, particularly via the tumor vasculature, exerts a major influence on cancer cell survival after radiotherapy. Recent work by our groups has exploited fluorescence imaging of a live-cell reporter of DNA double strand breaks (DSBs) to follow DSB formation after irradiation and the kinetics of damage repair or persistence. Here, we will examine radiation response in xenograft tumors in mice and dissect cross-talk between cancer cells and stroma. We plan to leverage complementary approaches developed in our laboratories to examine radiation response within the tumor microenvironment and then to examine the relationship between the heterogeneity of local events and overall response of tumors. Specifically, members of our group have pioneered use of 1) fluorescent DSB reporters to track DNA damage and repair in cancer cells within tumors, 2) transgenic nude mice with fluorescent stroma or vascular cells to track angiogenesis in tumors, 3) microarray analysis that can distinguish the gene expression patterns in the cancer and stromal cells, 4) advanced approaches to PET/MRI/CT and image integration to track tumor responses to targeted radiation, and 5) in vitro and computational modeling of determinants of tumor cell oxygenation and metabolism. By integrating these tools, we anticipate pursuing a multi-scale analysis and modeling of cellular proliferation vs. arrest, factoring in intrinsic determinants of DNA damage and repair and the effects of vascular geometry and angiogenesis at the level of microenvironment. We hope to project these events over time onto tumor size and metabolism on a gross level.
Radiation therapy is a widely used treatment for cancer, but cures a minority of patients. One hypothesis is that inadequate blood flow in tumors protects some cells from radiation. This project will use advanced imaging methods to examine how radiation affects cancer cells in experimental tumors, and how this relates to blood flow. We will then apply systems biology approaches to begin to model how cancer cells survive radiation and how we might achieve better results.
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