Genetics and Molecular Mechanisms of Prostate Cancer

我们进行了转译研究，以了解控制前列腺癌发生和发展的遗传和分子机制，确定药物开发的新途径，并调查耐药治疗范例的机制。我们与前列腺癌预防试验(PCPT)的研究人员长期合作，以阐明可能有助于解释PCPT试验结果的分子和遗传机制。该项目的总体目标是：a)更好地了解重要的雄激素调节基因多态性与CAP风险之间的关系；以及b)评估这些基因多态性和血清激素浓度对非那雄胺作为CAP化学预防药物的使用的影响。我们最近确定，雌激素相关基因中的SNV与前列腺癌风险之间的关联是复杂的，可能会被循环激素水平和非那雄胺治疗所改变。我们最新的遗传学研究是几个机构的合作努力，我们发现在不同种族的患者群体中，胚系BRCA2突变频率的增加与前列腺癌转移有关。我们对了解雄激素转运的分子遗传学也很感兴趣。有机阴离子转运蛋白OATP1B3由SLCO1B3编码，参与类固醇激素的转运。我们已经证明，与正常或良性增生性组织相比，前列腺癌过表达OATP1B3，常见的SLCO1B3 GG/AA单倍型与睾酮转运受损和CAP患者的生存改善有关。我们发现，在接受ADT治疗的CAP患者中，该转运体的多态增加了睾酮的输入，与较短的雄激素依赖时间相关。去势抵抗前列腺癌(CRPC)的肿瘤内睾酮浓度高于优生子男性的类似肿瘤；简单的扩散不能解释这一观察结果。我们最近进行了一些研究，以确定OATP1B3从头表达的雄激素摄取动力学、功能和临床相关性。我们发现前列腺癌中从头开始的OATP1B3表达推动了更大的雄激素摄取，并与之前的观察一致，即更大的OATP1B3活性会导致雄激素剥夺治疗抵抗的发展和总生存期的缩短。目前正在研究SLCO1B3转录的分子机制，包括转录因子复合体，这些转录因子复合体聚集在SLCO1B3启动子的不同调控元件上，驱动前列腺癌中OATP1B3的组织特异性表达。了解OATP1B3表达的潜在调控机制以及转运蛋白在前列腺癌进展中的作用将有助于将其发展为潜在的治疗靶点。为此，我们目前正在开发一种OATP1B3抑制剂筛选试验，该试验将被验证用于高通量筛选来自国家癌症研究所天然产物储存库的化合物。

We have conducted translational research to understand the genetic and molecular mechanism that govern prostate cancer development and progression, to identify novel pathways for drug development, and investigate mechanisms of resistance to treatment paradigms. We have a longstanding collaboration with the Prostate Cancer Prevention Trial (PCPT) investigators to elucidate the molecular and genetic mechanisms that may help explain the trial outcomes of the PCPT. The overall goals of this project are: a) to better understand associations between important androgen regulatory gene polymorphisms and CaP risk; and b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for CaP. We recently determined that associations between SNVs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment. Our most recent genetic study was a collaborative effort among several institutions where we found that increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population. We are also interested in understanding the molecular genetics of androgen transport. The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. We have shown that prostate cancer overexpresses OATP1B3 compared to normal or benign hyperplastic tissue, and the common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with CaP. We found that a polymorphism in this transporter increases testosterone import is associated with a shorter time to androgen independence in patients with CaP who are treated with ADT. Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. We recently conducted studies to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of OATP1B3. We found that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Studies are ongoing to characterize the molecular mechanisms of SLCO1B3 transcription including transcription factor complexes that assemble at distinct regulatory elements in the SLCO1B3 promoter for driving tissue-specific expression of OATP1B3 in prostate cancer. Understanding the underlying regulatory mechanisms of OATP1B3 expression and the transporter's role in prostate cancer progression will aid in its development as a potential therapeutic target. To this end, we are currently developing an OATP1B3 inhibitor screening assay that will be validated for use in a high-throughput screening of compounds from the National Cancer Institute's Natural Products Repository.