The long term objective of this project is to improve understanding of the role of hypoxia in tumor biology and tumors' response to therapy. The experiments are designed to quantify hypoxia in soft tissue sarcomas by PET imaging with {F-18]fluoromisonidazole (FMISO) and to correlate this with oxygen electrode measures and with biological characteristics of the tumor as well as patient outcome after treatment. Soft tissue sarcomas are heterogeneous tumors in which it is difficult to predict response to neoadjuvant chemotherapy given prior to surgery or to predict who will fail treatment with distant metastases. Measuring hypoxia in these tumors should be useful in understanding the natural history of sarcomas as well as their response to therapy, because tumor hypoxia affects expression of many genes and appears to be positively correlated with increased metastatic potential and local aggressiveness of both animal and human tumors.
The specific aims of the proposal are: (1) Perform pre-treatment FMISO scans and correlate with histological grade of tumors; (2) Correlate pre-chemotherapy FMISO scans in sarcomas with response to chemotherapy; (3) Correlate pre-chemotherapy FMISO scans (intermediate and high grade tumors) and pre-surgery scans (all tumor grades) with patterns of distant failure; (4) Compare oxygen electrodes to FMISO images for assessing tumor hypoxia; and (5) Determine the relative importance of hypoxia in relation to other factors in inducing the endothelial cytokine, vascular endothelial growth factor (VEGF). Hypoxia will be quantified as fractional hypoxic volume (FHV) determined from FMISO PET images. Tumor, histological grade, response to pre-surgery chemotherapy, and patient outcome will be assessed using standard clinical and histological endpoints. Microvascularity, cell proliferation, and expression of VEGF will be measured in post-surgical tumor specimens using immunohistochemistry. The effects of hypoxia and other inducers of VEGF in sarcomas also will be studied in cells cultured from primary tumors, using molecular and immunohistochemical techniques to examine gene and protein expression. In vitro studies will also be done on cultured cells from breast and brain tumors. Successful completion of this project will provide a better understanding of soft tissue sarcomas and will lay the basis for more rationale treatment decisions.
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