A New Mechanism for Castration Resistant Prostate Cancer

去势抵抗性前列腺癌的新机制

基本信息

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
项目类别：
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

项目摘要

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

首席研究员/项目主任（后、一、中）：孙子杰项目概要查尔斯·哈金斯 (Charles Huggins) 和克拉伦斯·霍奇斯 (Clarence Hodges) 发明雄激素已有近 60 年历史用于治疗前列腺癌的剥夺疗法。许多不同的药物已经被开发出来并此后应用于患者以实现雄激素减少或雄激素受体（AR）抑制，但雄激素剥夺背后的基本前提几乎没有改变。大多数患者会出现激素难治性肿瘤，也称为去势抵抗性前列腺癌 (CRPC) 在两到三年内开始治疗后，没有有效的治疗方法。肝细胞生长因子/分散因子（HGF/SF）是一种多功能生长因子，具有在细胞生长、细胞运动、形态发生和血管生成的调节中发挥关键作用。 HGF/SF发挥其通过其受体 c-Met（一种跨膜受体酪氨酸激酶 (RTK)）发挥作用。异常的表情 HGF/SF 和 c-Met 的存在通常与癌症患者的不良预后相关。旁分泌机制 HGF/SF 对 c-Met 的刺激很大程度上与前列腺癌的进展有关。它一直研究表明，HGF 显着增加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 的表达之间呈负相关已在前列腺癌细胞中观察到。据报道，阉割后的 c-Met 表达增加动物 8、14 以及转移性前列腺肿瘤样本中。这些数据表明 c-Met 在促进疾病进展、去势抵抗和转移。此前，我们的团队和其他人已经证明 AR 抑制前列腺中的 c-Met 表达癌细胞。具体来说，我们发现 AR 会中断 Sp1 诱导的 c-Met 转录激活。这些发现表明 AR 在转录激活子和抑制子中具有双重调节作用。前列腺癌细胞，并暗示前列腺癌进展的新分子机制。尽管雄激素消融疗法抑制 AR 诱导的生长促进基因表达的激活，它还减弱 AR 对 c-Met 表达的抑制作用并增加肿瘤细胞中的 c-Met。由于 c-Met 的过度表达与更具侵袭性的肿瘤表型直接相关，因此添加 c-Met 标准雄激素消融治疗的抑制剂可能会显着改善临床结果并延迟时间到 CRPC。因此，在这个 RO1 应用中，我们提出了三个独特但综合的具体目标来进一步测试我们的中心假设：通过同步雄激素消融疗法抑制 AR 活性可增加 c-Met 表达从而诱导前列腺癌的雄激素不敏感性和更具侵袭性的表型，以及 AR 和 c-Met 通路的共同抑制可以阻止或延迟 CRPC 的发展。主要目标是使用生物学相关系统将我们的实验室工作转化为临床工作，这将带来一种新颖的方法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 在前列腺癌形成和进展中的作用，2）作为原理证明，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的综合影响， 3）我们将进一步探索AR抑制c-Met表达的分子机制发现 AR 和 c-Met 途径中的未来治疗靶点。项目描述第6页