INTRA-TUMORAL METABOLIC HETEROGENEITY OF CERVICAL CANCER

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DESCRIPTION (provided by applicant): Patients with advanced cervical cancer are treated with chemoradiation. Pretreatment positron emission tomography (PET) with 18F- fluorodeoxyglucose (FDG) is routinely utilized for these patients to determine the extent of their disease, to aid in radiation treatment planning, and in follow-up after treatment. Tumor response determined by metabolic imaging with FDG-PET within three months after completing therapy is highly predictive of patient survival outcome. About 75% of patients will have a complete metabolic response and 25% will not. The purpose of this research is to characterize the PET-based metabolic parameters of complete and incompletely responding tumors. It has been shown that on a microscopic level, cervical cancers are heterogeneous. Evaluation of tumor microenvironments has demonstrated heterogeneity relating to variation in degree of vascularity, hypoxia, proliferation rates, energy metabolites, and gene expression. But, metabolic intra-tumoral heterogeneity across the entire volume of primary tumors in humans has not been quantified or analyzed for its association with treatment and outcome measures. PET images tumor metabolic function and presents a unique opportunity to evaluate inter- and intra-tumoral metabolic heterogeneity. The overall goal of this project is to test the hypothesis that novel PET-based metrics can evaluate intra-tumoral metabolic heterogeneity and define areas within tumors that will fail to respond to standard treatment with chemoradiation. This will be achieved by three specific aims: (1) further develop and validate a PET-based metrics to evaluate tumor FDG heterogeneity (glucose metabolism), (2) extend the use of this metric to PET with 3'-Deoxy-3'-18F-fluorothymidine (FLT) (marker of cellular proliferation) and PET with copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) (marker of assessment of hypoxia) to identify areas of metabolic concordance (or lack thereof) with FDG-PET, and (3) use these metrics to evaluate response during therapy and identify resistant areas within tumors. On completion, this project will provide a clinically validated PET-based metric to determine tumor heterogeneity for prediction of tumor responsiveness to therapy. Areas of differing metabolic responsiveness will be identified to further our understanding of the various biologic compartments within these tumors and to develop therapeutic strategies to overcome these areas of treatmen resistance. PUBLIC HEALTH RELEVANCE: Patients with advanced cervical cancer are treated with chemoradiation. Tumor response determined by metabolic imaging with FDG-PET within three months after completing therapy is highly predictive of patient survival outcome. About 75% of patients will have a complete metabolic response and 25% will not. The purpose of this research is to characterize the PET-based metabolic parameters of complete and incompletely responding tumors in order to develop therapeutic strategies to overcome these areas of treatment resistance.