Colin A. Flaveny, Ph.D. - US grants

Project Summary: Cancer cell metabolism comprises of a number of aberrantly regulated metabolic pathways including lipid synthesis (lipogenesis), glycolysis (the Warburg Effect). While prostate cancer PCa) cells do not exhibit elevated glucose uptake, a characteristic of the Warburg effect, they do feature elevated glycolysis and lipogenesis enzyme expression. Also whereas normal cells obtain lipids primarily from exogenous sources PCa cells depend on de novo lipid synthesis. Importantly, elevated glycolysis and lipogenesis enzyme expression drive metabolite production for nucleotide, protein and lipid production, which facilitate cell proliferation, energy production, intracellular signaling and immune evasion. Importantly lipogenesis and aberrant glycolysis enzyme expression have been identified, as bona-fide mediators of PCa etiology and invasiveness, therefore targeted disruption of these pathways are a potential treatment approach for PCa. A number of inhibitors have been developed to target cancer metabolism. Unfortunately these inhibitors have poor efficacy and have associated toxic side effects including severe weight-loss and anorexia in rodent cancer models. As a result there are currently no treatments for PCa that target oncogenic metabolism currently used in the clinic. PCa treatments that focus on blocking androgen receptor activity and cell division have not been able to extend patient lifespan substantially. This is due to PCa cells adapting and continuing to grow and invade other tissues by ?rewiring? androgen receptor signaling and bypassing targeted cellular pathways. Metastatic, castration resistant PCa is responsible for all PCa deaths. Therefore our objective is to develop a cancer metabolism inhibitor that is effective, safe and will be able to replace, supplement or enhance current treatments. We hypothesized that suppression of the transcriptional activity of the liver-X-receptor (LXR); a master regulator of expression of multiple glycolysis and lipogenesis genes could be a potent means of inhibiting cancer metabolism. Therefore we designed a LXR inverse agonist: SR9243 that suppresses LXR transcriptional activity. SR9243 significantly blocks the Warburg effect and lipogenesis and is able to disrupt PCa cell growth without producing weight loss or other undesired side effects. To investigate whether LXR inverse agonism, using SR9243, is a useful treatment approach for PCa we will address 2 specific aims. Specific Aim 1 will test the efficacy of SR9243 against PCa tumors in a PCa orthotopic primary tumor model and a metastatic model. Specific Aim 2 will investigate whether SR9243 is able to enhance the efficacy of currently used PCa treatments when used in combination using a patient derived xenograft model of PCa. This study should generate a novel treatment approach for PCa and will lay the foundation for future projects aimed at exploring the mechanistic role of LXR transcriptional activity in PCa metabolism.

Project Summary: Metastatic prostate cancer will claim the lives of over 30,000 men this year alone. There are no effective treatments that prevents disease progression. In prostate cancer, lipid production is known to drive tumor growth throughout the early and late stages. In addition to providing building blocks for tumor cell replication, lipids produced by tumors have been shown to repress immune activity, which allows tumors to grow unchecked. Clinically used immunotherapies which deactivate built-in anti- inflammatory pathways called immune checkpoints, have been highly effective at harnessing the tumor- killing abilities of immune cells. Unfortunately checkpoint blockade inhibitors are notoriously ineffective at treating metastatic prostate cancer. Studies have shown that tumors produce lipid metabolites, endogenous ligands of Liver-X-Receptor (LXR) that activate and suppress the function of immune cells. In line with this shutting down production of lipid metabolites in tumor cells reverses tumor suppression resulting in tumor destruction. As prostate cancer cells rely heavily on lipid synthesis, we postulated that prostate tumors produce LXR ligands to suppress immune function. Our studies have highlighted that prostate tumors produce lipids that activate LXR and suppress the activity of helper and effector T-cells as well as dendritic cells, all key cell types that direct a robust anti-tumor immune response. We theorized that prostate tumors specifically produce high activity LXR ligands and by suppressing LXR activity in immune cells we could stimulate tumor destruction. In this proposal, we will explore this hypothesis using three specific aims. We propose firstly to identify if prostate tumors produce unique lipids, LXR ligands, that are especially effective at suppressing immune cell activity. We also intend to determine if the concentrations of specific tumor lipids correlate with disease severity or responsiveness to treatment. Secondly, we will test if drugs which suppress LXR activation, can stimulate destruction of prostate tumors when used alone and probe whether these drugs can sensitize prostate tumors to checkpoint immunotherapies. Lastly, we will determine how LXR signaling regulates immune cell metabolism and the manner in which immune cells respond to prostate tumor growth. These studies should lead to the development of a novel dual activity immunotherapy for prostate cancer that has intrinsic cytotoxicity and immune stimulatory activity.