Functional Genomics and Molecular Imaging of Liver Disease and Cancer

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DESCRIPTION (provided by applicant): HCC is the fourth most common cancer in the world and third leading cause of cancer mortality worldwide. In the United States, HCC incidence continues to increase with an estimated 24,120 new cases diagnosed in 2010. The prognosis for this disease is poor even at early stage with a 5 year survival of 26% compared to only 2% when it is metastatic. Surgery is considered the best treatment option for hepatocellular carcinoma, but only if the disease is caught early and has not metastasized. Unfortunately, current imaging strategies for hepatocellular carcinoma (HCC) have a tendency to underestimate disease burden and extent, exposing patients who are not true surgical candidates to unnecessary morbidity, risks, and expense. Many patients with HCC also have underlying liver fibrosis or cirrhosis, and the health of the remnant liver is important in determining whether surgery is tolerable. Imaging also has not played enough of a role in assessing or predicting residual liver function in patients who are deemed surgical candidates. In addition, with the advent of molecular therapies for HCC such as sorafenib, imaging has not yet found a place in predicting or monitoring HCC response to therapeutic agents. The NIH Action Plan for Liver Disease Research calls for the development of new imaging techniques that can be applied clinically to HCC and chronic liver disease, and has identified Positron Emission Tomography (PET) as a promising technology that may address some of these issues. Unregulated phosphocholine synthesis is a feature found in many cancers that has also been observed in HCC. It is the target for a number of novel diagnostic and therapeutic strategies under development. How- ever, it is not certain at this time whether the changes in choline phospholipid metabolism are due to an in- creased demand for membrane phospholipids or an increase in mitogenic signaling, given that phosphocholine is both a membrane phospholipid and important second messenger in Ras mediated mitogenic pathways such as the MAPK and PI3K-AKT-mTOR pathways. The detection of both primary and metastatic HCC on the basis of enhanced tumor phosphocholine synthesis is feasible using positron emission tomography (PET) with the investigational tracer substrate of choline kinase, [18F]-fluoromethylcholine (FCH). However, the overall accuracy of FCH PET for HCC has not been formally tested, and the molecular mechanisms leading to choline kinase up regulation are still not yet determined for HCC. The aims of the proposed project are to: 1) Conduct a radiologic-pathologic correlation study collecting fresh frozen liver tissue specimens for correlation with FCH PET/CT to evaluate its diagnostic performance as a liver imaging modality for HCC, 2) Longitudinally assess liver function and disease outcome in HCC survivors to evaluate the clinical value of FCH PET/CT as a measure of hepatocyte function and prognostic value of transcriptional signatures obtained at the time of surgical resection of HCC. This novel integration between functional genomics and the evaluation of FCH PET/CT will determine the relative importance of phosphocholine metabolism as a diagnostic and therapeutic target in HCC and chronic liver disease, and advance our knowledge of the molecular mechanisms associated with the initiation and progression of HCC. This proposal is submitted in response to NIH PA-08-243.