Identify SNPs and Polymorphisms that are Important in th

识别重要的 SNP 和多态性

• 批准号: 7055447
• 负责人: William Douglas Figg
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7055447
• 关键词: androgen receptor; androgens; cancer risk; cell line; chemoprevention; finasteride; gene expression; gene mutation; genetic polymorphism; hormone metabolism; hormone regulation /control mechanism; hormone related neoplasm /cancer; human genetic material tag; metastasis; neoplasm /cancer genetics; neoplastic cell; neoplastic process; prostate neoplasms; receptor binding; single nucleotide polymorphism

It is well known that androgen deprivation is the cornerstone of initial therapy for metastatic prostate cancer. Once metastatic prostate cancer progresses in the face of hormonal therapy, it is classified as being androgen independent. Therapeutic options for patients with androgen independent prostate cancer are extremely limited. In particular, cytotoxic chemotherapy has provided minimal benefit. The purpose of this project is to perform translational research to develop new agents, and/or therapeutic maneuvers, that appear to have antitumor activity in prostate cancer. To achieve this goal, we have become extensively involved in the efforts to understand the biology of prostate cancer. Currently, we are attempting to correlate biological variables associated with prostate cancer and response to therapy (e.g., mutated androgen receptor, CAG repeats and microvessel count). The Molecular Pharmacology Sectionreported the first confirmation of the therapeutic efficacy of flutamide withdrawal, as well as the enhanced activity of simultaneous adrenal suppression. It has been hypothesized that the clinical improvement associated with flutamide is a result of the presence of a mutation within the ligand-binding domain of the androgen receptor. As we and others have reported, the human prostate cancer cell line LNCaP, which expresses such a mutated receptor, is stimulated to grow by hydroxy-flutamide, the active metabolite of flutamide. We believe that the mutation in the ligand-binding domain of the androgen receptor causes these normally antagonistic compounds to behave as androgen agonists. Whether this phenomenon is unique to the LNCaP cell line or is also responsible for the observations made in vivo is unknown. This question is being actively pursued in our section. More recently, we have initiated experiments in an attempt to determine which genes are regulated by the androgen receptor. In particular, we are interested in a polymorphism in the AR (a trinucleotide repeat in exon 1 -- CAG repeat). We are interested in analyzing several candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. All of the genes listed below have shown preliminary evidence that suggests that they may play important roles. Genes involved in the natural production of endostatin (COL18A1), the enzymes involved in testosterone processing (SRD5A1&2), drug metabolism (CYP3A4 &5), and genes involved in cellular transport and conjugation (UGT1A1, UGT2B15, UGT2B17) are being investigated for their involvement in the onset, progression and metastasis of prostate cancer.

众所周知，雄激素剥夺是转移性前列腺癌初始治疗的基石。一旦转移性前列腺癌在激素治疗的情况下进展，它被归类为雄激素非依赖性。雄激素非依赖性前列腺癌患者的治疗选择非常有限。特别是，细胞毒性化疗提供了最小的好处。该项目的目的是进行转化研究，以开发新的药物和/或治疗策略，似乎在前列腺癌中具有抗肿瘤活性。为了实现这一目标，我们广泛参与了了解前列腺癌生物学的努力。目前，我们正试图将与前列腺癌相关的生物学变量与对治疗的反应（例如，突变的雄激素受体、CAG重复序列和微血管计数）。分子药理学部分报道了首次确认氟替卡松停药的治疗效果，以及同时肾上腺抑制的增强活性。据推测，与氟替卡松相关的临床改善是雄激素受体配体结合域内存在突变的结果。正如我们和其他人所报道的那样，表达这种突变受体的人前列腺癌细胞系LNCaP被羟基氟替卡松（氟替卡松的活性代谢物）刺激生长。我们相信雄激素受体配体结合结构域的突变导致这些通常具有拮抗作用的化合物表现为雄激素激动剂。这种现象是否是LNCaP细胞系所特有的，或者也是体内观察结果的原因尚不清楚。我们部门正在积极探讨这个问题。最近，我们开始了实验，试图确定哪些基因受雄激素受体的调节。特别是，我们感兴趣的多态性在AR（一个三核苷酸重复外显子1 - CAG重复）。 我们感兴趣的是在基因组水平上分析几个候选基因的遗传变异，这些变异可能使个体患前列腺癌的风险增加。下面列出的所有基因都显示了初步证据，表明它们可能发挥重要作用。参与内皮抑制素天然产生的基因（COL 18 A1）、参与睾酮加工的酶（SRD 5A 1和2）、药物代谢（CYP 3A 4和5）以及参与细胞转运和结合的基因（UGT 1A 1、UGT 2B 15、UGT 2B 17）正在研究其参与前列腺癌的发生、进展和转移。