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。一旦前列腺癌在激素疗法面对荷尔蒙治疗时就会发展为独立的雄激素。独立前列腺癌患者的治疗选择极为有限。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/或治疗性动作，这些动作似乎在前列腺癌中具有抗肿瘤活性。为了实现这一目标，我们已经广泛参与了了解前列腺癌生物学的努力。目前，我们正在尝试将与前列腺癌和对治疗的反应相关的生物学变量（例如突变的雄激素受体，CAG重复序列和微血管计数）相关。分子药理学部分指出了氟丁酰胺戒断的治疗功效的首次确认，以及同时肾上腺抑制的增强活性。已经假设，与氟丁酰胺相关的临床改善是雄激素受体的配体结合结构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类前列腺癌细胞系LNCAP被羟基氟氨酰胺（氟氨酰胺的活性代谢产物）刺激。我们认为，雄激素受体的配体结合结构域中的突变会导致这些正常拮抗的化合物作为雄激素激动剂。该现象是LNCAP细胞系所独有的还是对体内进行的观察结果的原因，尚不清楚。这个问题正在我们的部分中积极提出。最近，我们开始了试图确定哪些基因受雄激素受体调节的尝试。特别是，我们对AR中的多态性感兴趣（外显子1- CAG重复中的三核苷酸重复）。 我们有兴趣分析基因组水平上的几个候选基因的遗传变异，这些变异可能使个体容易增加前列腺癌的风险。下面列出的所有基因均显示了初步证据表明它们可能扮演重要角色。参与自然产生内抑制素（COL18A1）的基因，参与睾丸激素加工（SRD5A1和2）的酶，药物代谢（CYP3A4和5）以及与细胞运输和结合的基因（UGT1A1，UGT2B15，UGT2B17）的参与及其相关的基因。 癌症。