A New Mechanism for Castration Resistant Prostate Cancer

去势抵抗性前列腺癌的新机制

• 批准号: 9233878
• 负责人: ZIJIE SUN
• 金额: $ 36.9万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233878
• 关键词: Ablation; Acetates; Address; Androgen Receptor; Androgens; Animals; Attenuated; Biochemical; Biological; Biological Testing; CYP17A1 gene; Cancer Patient; Castration; Cells; Clinical; Data; Development; Disease Progression; Future; Gene Expression; Genes; Genetic Transcription; Growth; HGF gene; Hormones; Lead; Malignant Epithelial Cell; Malignant neoplasm of prostate; Modeling; Molecular; Morphogenesis; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Principal Investigator; Promoter Regions; Prostatic Neoplasms; Proto-Oncogene Protein c-met; Receptor Protein-Tyrosine Kinases; Refractory; Reporting; Repression; Resistance; Role; Sampling; Signal Transduction; System; Technology; Testing; The Sun; Time; Transcription Coactivator; Transgenic Mice; Translating; Work; abiraterone; androgen independent prostate cancer; angiogenesis; base; castration resistant prostate cancer; cell growth regulation; cell motility; clinical application; deprivation; effective therapy; hormone therapy; improved; inhibitor/antagonist; meetings; men; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; paracrine; prevent; programs; prostate cancer cell; protein complex; public health relevance; receptor; response; single walled carbon nanotube; therapeutic target; tumor; tumor growth; tumor progression

Principal Investigator/Program Director (Last, first, middle): Sun, Zijie Project Summary It has been almost 60 years since Charles Huggins and Clarence Hodges invented androgen deprivation therapy for the treatment of prostate cancer. Many different medications have been developed and applied to patients to achieve androgen reduction or androgen receptor (AR) suppression since then, but the fundamental premise behind androgen deprivation has remained almost unchanged. Most patients develop hormone refractory tumor, also known as castration resistant prostate cancer (CRPC) within two to three years following initiation of therapy, for which there is no effective treatment. The hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that plays a critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. HGF/SF exerts its effects through its receptor, c-Met, a transmembrane receptor tyrosine kinase (RTK). The aberrant expression of HGF/SF and c-Met often correlates with poor prognosis in cancer patients. A paracrine mechanism for HGF/SF stimulation of c-Met has been largely implicated in the progression of prostate cancer. It has been shown that HGF significantly increases the proliferation, motility, and invasion of malignant epithelial cells through the c-Met protein. Interestingly, an inverse correlation between the expression of the AR and c-Met has been observed in prostate cancer cells. An increase in c-Met expression was reported in castrated animals 8, 14, and in metastatic prostate tumor samples. These data suggest a critical role for c-Met in promoting disease progression, castration resistance, and metastasis. Previously, our group and others have demonstrated that the AR represses c-Met expression in prostate cancer cells. Specifically, we identified that the AR interrupts Sp1-induced activation of c-Met transcription. These findings suggest a dual regulatory role for the AR as both a transcriptional activator and a repressor in prostate cancer cells, and imply a novel molecular mechanism for prostate cancer progression. While androgen ablation therapy suppresses activation of the growth promoting gene expression induced by the AR, it also attenuates the repressive role of the AR on c-Met expression and increases the c-Met in tumor cells. Since overexpression of c-Met directly correlates with more aggressive tumor phenotypes, adding c-Met inhibitors to standard androgen ablation therapy may significantly improve the clinical outcome and delay time to CRPC. Thus, in this RO1 application we propose three unique but integrated specific aims to further test our central hypothesis: Inhibition of AR activity through concurrent androgen ablation therapy increases c-Met expression thereby inducing androgen-insensitivity and more aggressive phenotypes of prostate cancer, and co-inhibition of AR and c-Met pathways can prevent or delay CRPC development. The major objective is to use biologically relevant systems to translate our bench work to the bedside, which will lead to a novel therapeutic strategy for treating advanced prostate cancer. Three specific aims are 1) we will directly assess the role of c-Met in prostate cancer formation and progression, 2) as proof-in-principle, we will directly determine the combined effects of c-Met inhibition and androgen ablation on prostate tumor growth and progression, and 3) we will further explore the molecular mechanism for AR repression of c-Met expression to discover future therapeutic targets in the AR and c-Met pathways. Project Description Page 6

首席调查员/计划总监（最后，第一，中间）：sun，Zijie 项目摘要 自查尔斯·哈金斯（Charles Huggins）和克拉伦斯·霍奇斯（Clarence Hodges）发明了雄激素以来已经快60年了。 治疗前列腺癌的剥夺疗法。已经开发了许多不同的药物 从那以后，适用于患者以实现雄激素还原或雄激素受体（AR）抑制 雄激素剥夺背后的基本前提几乎保持不变。大多数患者发展 激素难治性肿瘤，也称为抑制前列腺癌（CRPC）在两到三年内 启动治疗后，没有有效的治疗。 肝细胞生长因子/散射因子（HGF/SF）是一种多功能生长因子 在调节细胞生长，细胞运动，形态发生和血管生成中的关键作用。 HGF/SF发挥其作用 通过其受体C-MET的作用，跨膜受体酪氨酸激酶（RTK）的作用。异常表达 HGF/SF和C-MET的癌症通常与癌症患者的预后不良相关。旁分泌机制 HGF/SF刺激C-MET已在很大程度上与前列腺癌的进展有关。它一直 表明HGF显着增加了恶性上皮细胞的增殖，运动和侵袭 通过C-MET蛋白。有趣的是，AR和C-MET的表达之间的反相关性 已经在前列腺癌细胞中观察到。 cast割报告了C-MET表达的增加 动物8、14和转移性前列腺肿瘤样品中。这些数据表明C-MET在 促进疾病的进展，抑制性和转移。 以前，我们的小组和其他人已经证明了AR在前列腺中抑制C-MET的表达 癌细胞。具体而言，我们确定AR中断SP1诱导的C-MET转录激活。 这些发现表明AR作为转录激活剂和阻遏物在AR中的双重调节作用 前列腺癌细胞，这意味着前列腺癌进展的新型分子机制。尽管 雄激素消融疗法抑制了促进AR诱导的生长基因表达的激活 它还减轻了AR在C-MET表达中的抑制作用，并增加了肿瘤细胞中的C-MET。 由于C-MET的过表达直接与更具侵略性的肿瘤表型相关，因此增加了C-MET 标准雄激素消融疗法的抑制剂可能会显着改善临床结果和延迟时间 到CRPC。因此，在此RO1应用中，我们提出了三个独特但集成的特定目的，以进一步测试 我们的中心假设：通过并发雄激素消融治疗抑制AR活性会增加C-MET 表达表达，从而诱导雄激素不敏感性和前列腺癌的更具侵略性的表型，并且 AR和C-MET途径的共抑制可以预防或延迟CRPC的发展。主要目标是 使用生物学相关的系统将我们的长凳工作转换为床边，这将导致新颖 治疗晚期前列腺癌的治疗策略。三个具体目标是1）我们将直接评估 C-MET在前列腺癌的形成和进展中的作用，2）作为原则上的证明，我们将直接 确定C-MET抑制和雄激素消融对前列腺肿瘤生长和 进展，3）我们将进一步探索AR抑制C-MET表达的分子机制 在AR和C-MET途径中发现未来的治疗靶标。 项目说明第6页