The long term goals of this project are to develop improved, second generation radiopharmaceuticals to quantify hypoxia and increased cell proliferation, two properties of tumors likely to be associated with more aggressive growth. The first specific aim will compare the O2 dependent binding of a new nitroimidazole-based hypoxia probe, [F-18]fluoroetanidazole (FETA), to [Cu-64]ATSM, which is reported to bind more rapidly and at slightly higher O2 levels than the lead hypoxia tracer, [F-18]FMIS0. ATSM may allow detection of the moderate hypoxia (approaching 10 mm Hg) believed important in promoting more aggressive tumor growth and metastases.
Specific Aim 1 also proposes to synthesize and test congeners of FETA that are retained at higher oxygen levels, comparable to those allowing retention of ATSM. The second specific aim is to assess the level of hypoxia that induces genes such as VEGF, implicated in tumor invasiveness and poor clinical prognosis, and the key hypoxia-induced transcription factor, HIF-1. These studies will test the hypothesis that genes associated with tumor progression are upregulated at O2 levels higher than the severe hypoxia (less than 3 mm Hg) implicated in radiation resistance and detectable with current generation hypoxia tracers.
The third aim will evaluate the thymidine analog [F-18]3'-deoxy-3'-fluorothymidine (FLT) as a tracer of both cell proliferation and tumor aggressiveness. FLT uptake is dependent on the cell cycle regulated enzyme thymidine kinase 1 and, unlike [C-11]thymidine, its detection is not complicated by small molecular weight breakdown products. FLT uptake is hypothesized to be not only greater in proliferating than nonproliferating cells but also to rank more aggressive tumors greater than less aggressive tumors greater than normal cells, due to thymidine kinase deregulation as a function of malignant progression. The proposed studies will employ cultured human and rodent tumor lines as well as normal cells and transplanted rodent tumors. Cells with wild type or mutant p53, and cells transfected with HPV16E6 to abrogate p53 function, will be used for FLT studies correlating uptake with more malignant phenotype. Taken together, these studies will characterize new tracers that help identify more malignant tumors and aid in understanding the relationship between tumor microenvironment and the genetic basis of malignant progression.
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