Genetics and Molecular Mechanisms of Prostate Cancer

我们进行了转化研究，以了解控制前列腺癌发生和进展的遗传和分子机制，确定药物开发的新途径，并研究对治疗范式的耐药机制。随着靶向治疗药物（olaparib和rucaparib）的批准，前列腺癌进入了精准医学时代。生殖系突变的存在对前列腺癌患者具有重要的遗传性癌症意义，生殖系检测在癌症筛查、风险评估以及疾病的整体治疗和管理中越来越重要。我们感兴趣的是了解与遗传易感性、前列腺癌风险和结果相关的生殖系变异。随着治疗范式向精准医学的转变，了解影响前列腺癌生物学和风险的生殖系（可遗传）突变的作用以及这些改变对潜在治疗的后续影响至关重要。我们与前列腺癌预防试验（PCPT）的研究人员长期合作，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)更好地了解重要雄激素调节基因多态性与前列腺癌风险之间的关系；b)评估这些多态性和血清激素浓度对使用非那雄胺作为PCa化学预防剂的影响。目前正在研究肥胖相关的血清标志物在调节肥胖与前列腺癌风险之间的关系方面的作用。肥胖与前列腺癌相关的分子机制涉及类固醇激素和胰岛素/胰岛素样生长因子1 （IGF1）途径。我们调查了循环血清标志物（如雄激素和IGFs/ igfbp）与BMI的关系，以及肥胖与前列腺癌风险的关系。本巢式病例对照研究的数据和标本来自前列腺癌预防试验，这是一项非那雄胺用于前列腺癌预防的随机、安慰剂对照试验。通过前列腺活检确定是否存在癌症。检测血清性类固醇激素浓度和IGF1轴分析。Logistic回归估计了总体、低级别（Gleason 2-6）和高级别（Gleason 7-10）癌症风险的优势比和95% ci。我们发现BMI与血清类固醇和IGFs/ igfbp之间存在显著关联；IGF1轴与几种血清类固醇显著相关。血清类固醇水平不影响BMI与前列腺癌风险的关系；然而，IGFBP2和IGFs改变了肥胖与低级别和高级别疾病的关联。虽然血清类固醇和igf / igfbp与BMI相关，但只有IGF1轴与肥胖相关的前列腺癌风险有关。了解肥胖与前列腺癌风险的生物学机制，因为它与循环血清标志物有关，将有助于制定有效的前列腺癌预防策略和治疗方法。随着癌症基因组学时代的扩展，不同种族的前列腺癌发病率和死亡率不成比例的比例在临床环境中显示出越来越大的相关性。虽然黑人男性受影响最大，但历史数据显示，亚洲男性的情况正好相反，从而为探索可能涉及调解这些相反趋势的基因组途径奠定了基础。对种族差异的研究受到样本量的限制，但最近研究机构之间不断扩大的合作可能会改善这些不平衡，从而加强基因组学方面对健康差异的调查。在这项研究中，我们使用GENIE数据集进行了种族基因组学分析，以调查原发性和转移性患者肿瘤样本中选定基因的突变和拷贝数频率。此外，我们研究了TCGA种族队列，进行了祖先分析，并进行了转录组学分析，以确定在一个种族中高度上调而随后在另一个种族中下调的差异表达基因。我们的研究结果强调了以种族为特征的通路导向的基因突变频率，进一步，我们确定了黑人和亚洲男性之间表达差异的候选基因转录本。我们对了解雄激素运输的分子遗传学也很感兴趣。由SLCO1B3编码的有机阴离子转运体OATP1B3参与类固醇激素的转运。我们已经证明，与正常或良性增生组织相比，前列腺癌过度表达OATP1B3，常见的SLCO1B3 GG/AA单倍型与CaP患者睾酮转运受损和生存率提高有关。我们发现，这种转运体的多态性增加了睾酮进口，与接受ADT治疗的CaP患者较短的雄激素独立时间相关。去势抵抗性前列腺癌（CRPC）的瘤内睾酮浓度高于来自性腺正常男性的类似肿瘤；简单的扩散不能解释这一观察结果。我们最近进行了研究，以确定ooatp1b3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，在前列腺癌中，新的OATP1B3表达会导致更大的雄激素摄取，这与之前的观察结果一致，即更高的OATP1B3活性会导致雄激素剥夺治疗耐药性的发展和更短的总生存期。目前正在研究SLCO1B3转录的分子机制，包括转录因子复合物在SLCO1B3启动子中聚集在不同的调控元件上，以驱动OATP1B3在前列腺癌中的组织特异性表达。我们最近证明了一种新的mirna介导的阿比特龙诱导的SLCO1B3表达机制，这种转运蛋白也负责驱动雄激素剥夺治疗抵抗。了解通过差异miRNA表达介导的阿比特龙耐药机制也将有助于鉴定治疗耐药的潜在miRNA生物标志物和未来治疗方法的开发。我们目前也在研究基于细胞外囊泡（EV）的液体活检肿瘤标志物在CRPC疾病进展中的作用。

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. Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer, and germline testing is increasingly important in cancer screening, risk assessment, and the overall treatment and management of the disease. We are interested in understanding germline variants associated with inherited predisposition, prostate cancer risk and outcomes. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. 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 PCa risk; and b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for PCa. Studies are ongoing examining the effects of obesity-related serum markers on modulating the association of obesity with prostate cancer risk. Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor 1 (IGF1) pathways. We investigated the association of circulating serum markers (e.g. androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF1 axis analytes. Logistic regression estimated odds ratio and 95% CIs for risk of overall, low-grade (Gleason 2-6), and high-grade (Gleason 7-10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF1 axis was significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments. As the era of cancer genomics expands, disproportionate rates of prostate cancer incidence and mortality by race have demonstrated increasing relevance in clinical settings. While Black men are most particularly affected, as data has historically shown, the opposite is observed for Asian men, thus creating a basis for exploring genomic pathways potentially involved in mediating these opposing trends. Studies on racial differences are limited by sample size but recent expanding collaborations between research institutions may improve these imbalances to enhance investigations on health disparities from the genomics front. In this study, we performed a race genomics analysis using the GENIE dataset to investigate mutation and copy number frequencies of select genes in both primary and metastatic patient tumor samples. Further, we investigated the TCGA race cohort to conduct an ancestry analysis and performed transcriptomics analysis to identify differentially expressed genes highly upregulated in one race and subsequently downregulated in another. Our findings highlight pathway-oriented genetic mutation frequencies characterized by race and further, we identify candidate gene transcripts that have differential expression between Black and Asian men. 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. We recently demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression, a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will also assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics. We are also currently investigating the role of extracellular vesicles (EV)-based liquid biopsy tumor markers for CRPC disease progression.