讲座题目：Global approaches to identifying novel drug targets in prostate cancer
演讲人：Dieter A. Wolf
美国Sanford-Burnham医学研究所教授、蛋白质组学中心主任
时间：2014年3月31日上午9:30
地点：药学院426大会议室
内容摘要：
Wolf实验室的研究重点是基因转录调控机制，及其在肿瘤发生过程中的作用，并寻找抗癌药物的靶标。主要研究调控蛋白质的合成和泛素-蛋白酶体的蛋白质降解通路，及蛋白质的质量控制和相关应激反应的信号通路。最近发现一种新的药物先导化合物SMIP004，可以选择性地诱导前列腺癌细胞凋亡。这些研究将为研发癌症治疗药物带来关键性的技术。
Abstract
The Wolf lab seeks novel targets and small molecule compounds to combat castration resistant prostate cancer (CRPC).Prostate cancer is the most common male malignancy in the Western World and the second most common cause of cancer-related death in men. Standard care for advanced prostate cancer is androgen deprivation therapy (ADT). While most patients initially respond to ADT, virtually all - about 75,000 per year - develop incurable CRPC. On the basis that CRPC continues to depend on androgen receptor (AR) function, the AR pathway remains the Achilles’ heel of CRPC. Since existing small molecules AR blockers, while effective initially, are rapidly rendered inactive due to AR point mutations, new modalities of interfering with AR function are urgently needed.
We have recently discovered compoundSMIP004, a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. Chemogenomic and proteomic profiling (performed at SBMRI Cancer Center cores) revealed that the compound induces a pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, elicits cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation, drives transcriptional downregulation of the AR, and activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response pathway. SMIP004 potently inhibits the growth of prostate cancer xenografts in mice. Our current work focuses on the further development of SMIP004 and on the identification of other compounds with a novel mechanism of action against prostate cancer.
Many of the novel drug targets we are pursuing are components of stress response pathways. Cancer cells are typically subjected to stressful conditions in their tumor microenvironment, and yet escape stress-induced cell death mechanisms. We study how normal cells respond to stress and how stress response pathways are altered in cancer cells to enable their survival. In collaboration with the Functional Genomics core, we are also exploring ways of exploiting the stress phenotype of cancer cells and associated vulnerabilities for synthetically lethal drug targeting. The basic framework of these studies is built on understanding molecular mechanisms of protein homeostasis and quality control, principally pathways regulating protein synthesis and protein degradation through the ubiquitin-proteasome system. In these studies, we are frequently employing network analysis and modeling in collaboration with our colleagues from the NIH-funded San Diego Center for Systems Biology.
