New review from Sam Denmeade (of BAT fame) & Laura Sena [Johns Hopkins] [1]:
Fatty acid synthesis in prostate cancer: vulnerability or epiphenomenon?
Fatty acid synthase (FAS) is an enzyme used to synthesize fatty acids - primarily palmitic acid, which can be elongated to produce a number of other fatty acids.
Oddly, FAS is an early feature of PCa development, even when an ample supply of fatty acids is in circulation.
I have long been interested in FAS. Seems that it should be a target. Was identified as such in a 1995 paper [2], but nothing much seems to have happened since:
[2] OA-519 (fatty acid synthase) as an independent predictor of pathologic state in adenocarcinoma of the prostate - Alan Partin [Johns Hopkins]
Extracts from the Denmeade paper:
A metabolic feature of many cancers is the ability to generate de novo fatty acids.
A comparison of gene expression of 32 cancer types ... indicates that compared with other types of cancer, primary prostate cancer exhibits high expression of key proteins in the fatty acid synthesis pathway.
FASN {the FAS gene} expression is undetectable ... in benign prostate and nearly uniformly positive across prostatic intraepithelial neoplasia (PIN) and invasive carcinomas, and with particularly high expression in metastatic tumors.
Evidence that prostate cancer may engage in high rates of fatty acid synthesis begs the question of whether activation of this pathway is important or incidental (i.e. an epiphenomenon) to prostate cancer development and progression. The former is suggested by the positive correlation between levels of fatty acid synthesis enzymes and products and prostate cancer disease stage. In fact, FASN expression level predicts seminal vesicle invasion or lymph node metastases, independent of Gleason score, in primary prostate cancer. Among patients with PTEN loss, high FASN expression was associated with shorter overall survival .
Inhibition of fatty acid synthesis has been proposed as a viable therapeutic strategy for treatment of cancer because activation of this pathway seems to be restricted to a limited number of normal tissues in adults, potentially creating an acceptable therapeutic index. Fatty acid synthesis can be inhibited directly by inhibiting the enzymes in this pathway or, perhaps indirectly, by activating AMPK. {Note that Metformin & Berberine are activators of AMPK.}
TVB-2640 is an oral, reversible inhibitor of the β-ketoacyl reductase domain of the FASN enzyme complex being developed by Sagimet Biosciences. It has been tested in a phase I clinical trial for patients with advanced solid tumors as monotherapy or in combination with a taxane (112). This study suggested TVB-2640 engaged the target and was safe, with the dose- limiting toxicities being skin and ocular effects. This agent has also been tested in a phase I clinical trial for patients with obesity in which it was found to reduce hepatic de novo lipogenesis as assessed by acetate isotope tracing and decrease intrahepatic triacylglycerols (113). Results from a phase II study of TVB-2640 in combination with the VEGF inhibitor bevacizumab for patients with glioblastoma has been reported in abstract form at the European Society for Medical Oncology (ESMO) virtual conference 2020 and suggested this regimen was well tolerated and improved progression-free and overall survival compared with historical controls (114). Clinical trials are ongoing testing safety and efficacy of this agent for patients with KRAS- mutated non-small cell lung cancer (NCT03808558), resectable colon cancer (NCT02980029), and HER2-positive advanced breast cancer (NCT03179904). To our knowledge, there are no ongoing trials testing TVB-2640 in patients with prostate cancer.
An alternative strategy to inhibit fatty acid synthesis may be activation of AMPK, which can potently inhibit ACC. Metformin is an agent that is already approved by the US Food and Drug
Administration for use in humans that can lead to activation of AMPK and inactivation of fatty acid synthesis due to inhibition of mitochondrial complex I. Retrospective studies have suggested that, among diabetic patients with prostate cancer, those on metformin have better prostate cancer outcomes than those not on metformin. Yet prospective studies in patients with prostate cancer have been disappointing to date – the TAXOMET trial, a randomized phase II study of docetaxel and metformin versus docetaxel and placebo, suggested no benefit by the addition of metformin to docetaxel, and the MetAb-Pro trial, a single arm trial of metformin and abiraterone for patients progressing on abiraterone, suggested no benefit from metformin in this setting. These trials included limited correlative studies so the effect of metformin on prostate cancer cell metabolism in patients remains unclear, however inadequate potency and transport-mediated accumulation may limit efficacy. Recently a novel agent IAC-010759 was described to be a highly potent and selective small molecule inhibitor of mitochondrial complex I that leads to AMPK activation that can inhibit malignant cell growth in models of glioblastoma and acute myeloid leukemia. This agent was well tolerated in animal models, and initial reported results from the phase I clinical trial suggested good tolerance in humans with the most common side-effect being raised lactate without acidosis. The phase I trial included three patients with CRPC and reported one patient with heavily pretreated disease who exhibited a RECIST partial response and resolution of CRPC-related pain. Complex I inhibition has many effects on metabolism of cancer cells so it is unclear to what extent inhibition of fatty acid synthesis may contribute to efficacy of this agent.
Natural Inhibitors of FAS.
[Na] Epigallocatechin-3-gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells (2003, Belgium)
[Nb] Vitamin D3 inhibits fatty acid synthase expression by stimulating the expression of long-chain fatty-acid-CoA ligase 3 in prostate cancer cells (2004, Finland)
Pharmaceutical Inhibitors of FAS.
[Pa] Inhibition of fatty acid synthase activity in prostate cancer cells by dutasteride (2007, Mayo)
[Pb] Metformin-Induced Killing of Triple Negative Breast Cancer Cells is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b (2014, U.S.)
-Patrick
[1] cancerres.aacrjournals.org/...
[2] pubmed.ncbi.nlm.nih.gov/781...
[Na] pubmed.ncbi.nlm.nih.gov/129...
[Nb] pubmed.ncbi.nlm.nih.gov/155...
Entering Clinical Trials
Effects of Curcumin and Lactoferrin to Inhibit the Growth and Migration of Prostatic Cancer Cells
Question about availability of Lu-177 therapy
