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

首席研究员/项目主任（后、一、中）：孙子杰