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Growth Regulation and Prostate Cancer
Our laboratory is interested in gaining a better understanding of the growth regulation of prostate cancer and using this information to identify novel therapeutic and imaging targets for this disease. One aspect of our research focuses on new treatment strategies, such as endothelin receptor blockade, to combat advanced prostate disease. To date, hormone ablation is the most common treatment for advanced disease. Ablation initially decreases tumor size, but it does not result in a permanent remission and so the majority of patients eventually present with recurrent hormone-refractory tumors. Endothelin-1 (ET-1) has been identified as an important growth factor in the pathophysiology of androgen-refractory prostate cancer. These findings have been applied to the clinic, and trials using endothelin receptor blockade have demonstrated significant clinical benefit in patients with advanced prostate cancer. We have shown that both ET-1 and one of its receptors, ETA, undergo up-regulation after androgen ablation. Moreover, activation of the ETA signaling pathway results in inhibition of apoptosis. These observations have led to our hypothesis that the ET axis provides a survival mechanism for prostate cancer cells facing androgen ablation; a key event in the evolution of androgen-refractory disease. Continuation of our work involving the endothelin axis includes further characterizing ET-1 signaling pathways in prostate cancer and expanding the therapeutic targets for prostate cancer treatment. These studies will also help identify those patients most likely to respond to endothelin receptor blockade through analysis of the ET axis. Other research interests include the co-modulation of bone and prostate cancer cell growth. Metastatic prostate cancer commonly resides in the bone during the progression of androgen refractory disease. Our laboratory is examining bone cell/prostate cancer cell interactions to further identify new mechanisms for therapeutic intervention for prostate cancer patients with metastatic disease to the bone.
Fatty Acid Synthase and Prostate Cancer
In addition to the studies on the endothelin axis, our laboratory is also pursuing studies in altered cell metabolism during prostate cancer progression. Fatty acid synthase (FAS) is the major multifunctional enzyme required by cells to convert carbohydrates to fatty acids de novo. FAS protein levels and enzyme activity are low in most normal tissues, but become up-regulated in prostate cancer. Our studies investigate the role of FAS and lipids during androgen-dependent and -independent prostate tumorigenesis using in vitro and transgenic mouse models, and examine the effects of FAS anti-metabolite therapy on cell death and tumor regression. Overexpression of FAS in prostate cancer cells also makes this molecule a potential imaging target for positron emission tomography (PET). Thus, our laboratory is exploring the use of PET imaging for the study of FAS in local and metastatic prostate tumors, with the ultimate goal of developing this technique into a method for imaging advanced disease.
For more information regarding graduate work in my lab, please go to the University of Pittsburgh Graduate faculty website (http://path.upmc.edu/cmp/fac43.htm)
Selected Publications
