Cancer imaging based on tissue biomarkers of phosphocholine synthesis

Abstract

Phosphocholine synthesis is upregulated in a variety of cancers as a means of supplying phosphatidylcholine for cell membrane proliferation and alternatively as a source of phospholipid second messengers for mitogenic and apoptosis-related signal transduction. This has made phosphocholine synthesis an attractive molecular target for cancer therapeutics and diagnostics. Flurorine-18 fluorocholine (FC) is an investigational derivative of choline designed as an imaging tracer for positron emission tomography (PET). Tissue uptake of FC has been shown to parallel phosphocholine synthesis since, like choline, FC is transported by membrane choline transporters and phosphorylated by choline kinase (CK). Hepatocellular carcinoma (HCC) is a primary tumor of the liver and one of the most common cancers worldwide. Hepatocarcinogenesis is known to involve abnormal signaling in multiple molecular pathways, including those that rely on phosphocholine as a second-messenger. This dissertation advances the concept of phosphocholine synthesis as an imaging biomarker of HCC by testing the feasibility of clinically detecting HCC by FC PET. A 2-tissue compartment model for describing the tissue pharmacokinetics of FC was proposed and tested by fitting this model to liver PET imaging data from patients with HCC. Various methodological aspects of dynamic PET image feature extraction were tested, including partial-volume effect, temporal resolution, and image-derived arterial input function reliability. The results of parametric modeling indicated that HCC could be distinguished from non-neoplastic hepatic tissue by the blood-to-tissue influx constant (k1) reflecting the activity of the membrane choline transporter. To determine if over-expression of choline transporter could be the mechanistic basis for the increase in this PET-imaging kinetic parameter in HCC, an independent study using tissue micro-arrays examined CK and choline transporter protein expression in HCC tumors. An immunohistochemical comparison between archival liver tumor specimens and corresponding non-neoplastic hepatic tissues revealed over-expression of the choline transporter, and to a lesser extent CK, in HCC. Translocation of the choline transporter to the nuclei of neoplastic cells was also discovered in this analysis. Altogether, the results of this dissertation provide a mechanistic basis for the upregulation of phosphocholine synthesis as a novel imaging and tissue biomarker for HCC.