Metabolic reprogramming is a hallmark of many cancers. First observed by Warburg, tumor cells switch from mitochondrial oxidative phosphorylation (MOP) to aerobic glycolysis (AG). AG is less energy efficient than MOP, but it appears to confer advantages to rapidly proliferating cells through formation of metabolic by- products that can be incorporated into membrane lipids, signaling molecules, amino acids and nucleotides. Enzymes that contribute to de novo lipogenesis, the synthesis of fatty acids from acetyl-CoA, have been shown to be overexpressed in a number of human cancers. Fatty acid synthase (FASN) catalyzes the synthesis of palmitic acid from acetyl-CoA and malonyl-CoA and in recent years has been shown ex v ivo to be overexpressed in cancers, including breast, prostate, colorectal and glioma, and to contribute to drug resistance. Overexpression of FASN is associated with a poor prognosis. As e xpression of FASN in normal tissue is very low, and FASN appears to play an i mportant role in tumor proliferation and malignancy, it has been proposed as a therapeutic target in various cancers. Inhibition of FASN has been shown to induce apoptosis, reduce tumor growth and impart chemosensitivity in multiple cancers including breast and prostate. Clinical diagnosis of prostate cancer involves prostate-specific antigen blood screening and biopsy. Patients are typically stratified according to clinical T-score, PSA count and Gleason score. At present, it remains difficult to distinguish between patients with aggressive and indolent forms of the disease, and new biomarkers for prostate cancer are necessary to better predict outcome and response to therapy. FASN has been proposed as a promising candidate biomarker, but its relevance has not been assessed in vivo by non-invasive means. Positron emission tomography (PET) imaging is a r apidly growing diagnostic field that enables the non- invasive study of disease. This project proposes to develop a small series of FASN inhibitors labeled with carbon-11 or fluorine-18 for imaging FASN expression in prostate cancer cell lines and mouse xenograft models. To assess FASN expression, a series of novel tracers labeled with 11C or 18F will be synthesized based on the most potent FASN inhibitors reported to date. To our knowledge this project represents the first attempt to study FASN expression via molecular imaging using inhibitors of the enzyme. If successful, this program will provide new radiolabeled probes to identify and quantify FASN expression in vivo using non-invasive PET imaging. This capability will provide a tool to study FASN biology, identify FASN positive tumors and identify patients who may benefit from anti-FASN therapy. Significant prognostic value may be attained by noninvasive monitoring of FASN expression during disease progression and over the course of therapeutic interventions. This is particularly intriguing in light of the recent reports of FASN therapies in tumor bearing animals and promising antitumor effects in early clinical trials.
Proliferatively active cells require fatty acids for functions such as membrane generation, protein modification, and bioenergetics requirements. In particular, overexpression of the multi-enzyme complex fatty acid synthase (FASN) is common to many tumor cells and is often associated with poor prognosis. A series of small molecules inhibitors of FASN are proposed as PET radioligands for non-invasive in vivo imaging of FASN expression with a view towards the clinical development of an imaging biomarker for FASN expression in tumors.
