Our laboratory is interested in understanding tumor signaling and growth regulation in prostate cancer and uses this information to identify novel therapeutic and imaging targets for this disease. We use molecular and cell biology approaches, human tissue and cell lines as well as mouse models of prostate cancer to characterize targets and test potential new therapeutic and PET imaging agents. One aspect of the research lab focuses on altered cell metabolism during prostate cancer progression. Fatty acid synthase (FASN) is the major multifunctional enzyme required by cells to convert carbohydrates to fatty acids de novo. FASN protein levels and enzyme activity are low in most normal tissues, but become up-regulated in prostate cancer both before and after androgen ablation therapy. Our studies investigate the role of FASN and lipids during prostate tumorigenesis and progression using in vitro and mouse models of prostate cancer to test the molecular effects of elevated pathway activity, gain understanding of how this pathway is regulated in cancer and assess the effects of FASN pathway inhibition on tumor progression using anti-metabolites.
The lab is also interested in the role of the endothelin axis in progression to advanced prostate cancer. Understanding the mechanisms in which prostate cells become invasive and hormone refractory is vital to identifying key targetable pathways of prostate cancer progression and design new therapeutic strategies. The endothelin axis (ET-1, ETA-R and ETB-R ) has an important role in prostate cancer progression by providing a growth/survival response in prostate cancer cells, and this work has uncovered a potential role of stromal involvement in conditioning the prostate cancer cells for survival in the bone microenvironment. Our goal is to understand the contributions of this pathway to prostate cancer and implement these findings to improve upon potential therapeutic protocols capable of attenuating disease progression.
We also are interested in translocator protein (TSPO), a mitochondrial transmembrane molecule implicated in the progression of several epithelial tumors, including prostate cancer. The multifunctional TSPO (also known as peripheral benzodiazepine receptor-PBR) contributes to the regulation of proliferation, apoptosis and inflammation, but is best known for transporting cholesterol across the mitochondrial membrane for cell signaling and steroid biosynthesis. We have identified elevated TSPO in prostate cancer tissue and cell lines and have found that it functions, in part, as a survival factor for prostate cells and hypothesize that disruption of the TSPO pathway in prostate cancer will attenuate disease progression as TSPO appears to be involved in several important functional pathways, including steroidogenesis, metastasis and apoptosis. We have tested cancer cell sensitivity to TSPO blockade by screening a series of potential TSPO antagonists, including benzodiazepines and are now developing new compounds that target TSPO while avoiding CNS targets and are pursing TSPO as a target for PET imaging.
Identification and characterization of novel therapeutic targets and understanding cancer microenvironment in advanced prostate cancer including:
- mechanisms of dysregulation of lipid synthesis via fatty acid synthase (FASN), development of pathway inhibitors and identification of FASN regulated pathways in cancer
- role of the endothelin axis in stromal contribution to conditioning prostate cancer cells for survival in the bone microenvironment, role in development of androgen refractory prostate cancer, and endothelin receptor antagonism as a therapeutic target for prostate cancer
- determine the functional consequences of altered translocator protein (TSPO) in cancer progression, investigate the role of TSPO-regulated cholesterol transport during androgen refractory disease progression and develop TSPO as an imaging target for prostate cancer
Zhao H, Pflug B, Lai X, Wang M. (2015) Metabolic and molecular regulation of dietary polyunsaturated fatty acids on prostate cancer. Proteomics-Clinical Applications (accepted).
Fako V, Wu X, Pflug B, Liu J-Y, Zhang J-T. (2015) Repositioning Proton Pump Inhibitors as Anti-Cancer Drugs by Targeting the Thioesterase Domain of Human Fatty Acid Synthase. J Medicinal Chemistry. 58(2); 332-338.
Fafalios A, Akhavan A, Parwani AV, Bies RR, McHugh KJ, and Pflug BR (2009) Translocator protein blockade reduces prostate tumor growth. Clinical Cancer Research 15: 6177-6184.
D'Antonio JM, Ma C, Monzon FA and Pflug BR (2008) Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence. The Prostate 68(7):698-714.
Akhavan A, McHugh KH, Guruli G, Bies RR, Zamboni WC, Strychor S, Nelson JB and Pflug BR. (2006) Endothelin receptor A blockade enhances taxane effects in prostate cancer. Neoplasia 8: 725-732.