Imaging Signaling Changes in Cancer and Treatment

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DESCRIPTION (provided by applicant): The most common brain tumors are gliomas, and the most common malignant variant is glioblastoma multiforme (GBM). The absence of effective therapy for this tumor requires a better understanding of the biology of glioma formation and progression. Recent studies have identified abnormal signaling pathways in gliomas and transgenic animal models have shown that some of these signaling abnormalities are causally related to glioma formation and progression. The overall aim of the proposed research is to build on these recent findings and to develop noninvasive in vivo reporter imaging systems that can be used in the study malignant transformation (oncogenesis) of gliomas and other tumors, and for the assessment of targeted drug therapy. We plan to develop and validate methods for non-invasive optical and radionuclide imaging of PDGF and EGFR signaling through the Ras/Raf/MEK/Erk- and PKB/Akt/mTOR-mediated pathways in transduced cell lines and tumor-bearing animals. This proposal combines established transgenic animal models of gliomas that exist at our institution (Dr. E. Holland) with the molecular imaging experience of the applicant's laboratory. Specifically, we plan to develop multi-modal reporter systems for both optical- and radionuclide based imaging that will be validated by a series of in vitro and in vivo experiments and molecular assays. We plan to develop and study transgenic animals expressing these reporter systems, and then develop double-transgenic reporter animals in order to: 1) image aberrant signaling and pathway activity during oncogenesis, and 2) image and monitor signal pathway activity during targeted drug therapy. The potential benefits of developing transgenic animals bearing signal transduction reporter systems are substantial. Once developed, these reporter systems and the transgenic animals bearing the reporter systems can be used to study oncognesis in different organ systems and could be useful in the study of other disease processes as well. The ability to image and monitor signal transduction pathway activity during targeted drug therapy offers a new approach to the assessment of drug efficacy in animal models. This can be performed in vivo and noninvasively, and may be particularly useful in the assessment of cytostatic drugs.