Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.

免疫炎症信号传导和激素难治性前列腺癌的演变。

基本信息

批准号：
8235834
负责人：
Jun-Li Luo
金额：
$ 40.57万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235834
关键词：
Adenocarcinoma Adjuvant Affect Agonist Alleles Allografting Androgens Anti-Inflammatory Agents Anti-inflammatory Antibodies Aspirin B-Lymphocytes Biological Assay CD19 gene Cancer Center Carcinoma Castration Cells ChIP-on-chip Clinical Collaborations Consumption Cooperative Human Tissue Network Dendritic Cells Development Disease Epidemiologic Studies Epithelial Cells Evolution Foundations Genetic Transcription Genotype Goals Growth Health Hepatocyte Hormones Human Immune Inflammatory Inflammatory Response Local Therapy Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Modeling Molecular Genetics Molecular Profiling Mus Nuclear Nuclear Translocation Participant Pathologist Pathway interactions Patients Pharmaceutical Preparations Prevention Production Prostate Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Radiation therapy Radical Prostatectomy Rag1 Mouse Refractory Research Resistance Role Signal Pathway Signal Transduction Staging Systemic Therapy T-Lymphocyte Testing Transgenic Organisms Transplantation Tumor Necrosis Factor-Beta Xenograft procedure advanced disease androgen independent prostate cancer autocrine base cancer cell cancer risk chemokine cytokine deprivation effective therapy high risk hormone refractory prostate cancer insight macrophage men mouse model neoplastic cell novel therapeutic intervention novel therapeutics promoter response small hairpin RNA transcription factor treatment strategy tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a heterogeneous disease that progresses from prostatic intraepithelial neoplasia to locally invasive adenocarcinoma and then to hormone-refractory carcinoma. In tumors confined to the prostate, radical prostatectomy and radiotherapy are effective. However, no effective treatments are available for hormone-refractory PCa. Androgen deprivation therapy (ADT) is initial systemic therapy for advanced PCa and is used as an adjuvant to local therapy for high-risk disease, but, tragically, responses in advanced disease are only transient. Thus, research on the mechanisms of hormone refractory PCa formation, especially studies that are likely to result in novel therapeutic approaches, is of great importance. In our Preliminary Studies, selectively blocking NF-?B, the principle inflammatory transcription factor, in immune cells, dramatically impairs the development of castration resistant prostate cancer (CR-PCa) in both transgenic and xenograft PCa mouse models. We also found that one of the critical participants in this inflammatory response is tumor infiltrating B cells, which produce LTa:¿ heterotrimers that stimulate LT¿R on PCa cells to induce IKKa nuclear translocation and activation, thereby enhancing androgen-independent growth. Accordingly, we propose to define how LTs and LTs-induced IKKa nuclear translocation and activation mediate the formation of CR-PCa, and the relevance of LTs expression, IKKa nuclear localization and activation to human prostate cancer. We believe our studies will provide new insights into how B cells-derived LTs control CR-PCa, and will lay the foundation for developing novel therapeutic strategies for the treatment and/or prevention of hormone refractory PCa. PUBLIC HEALTH RELEVANCE: The goals of the proposed research are to define the roles of lymphotoxin (LT)-directed signaling in controlling the development of androgen-independent (AI) prostate cancer (PCa), which is essentially an incurable malignancy. Using state-of-the-art genetic and molecular approaches, the proposed studies will provide new insights into how LT-directed signaling regulates AI PCa formation, and we firmly believe that these studies will lay the foundation for developing novel therapeutic strategies for the treatment and/or prevention of hormone refractory prostate cancer.

描述（由申请人提供）：前列腺癌（PCa）是一种异质性疾病，从前列腺上皮内瘤变进展为局部浸润性腺癌，然后进展为局限于前列腺的肿瘤，根治性前列腺切除术和放射治疗是有效的。对于激素难治性 PCa 没有有效的治疗方法，雄激素剥夺疗法 (ADT) 是晚期 PCa 的初始全身治疗，并被用作一种治疗方法。作为高危疾病局部治疗的辅助治疗，但不幸的是，晚期疾病的反应只是短暂的，因此，对激素难治性 PCa 形成机制的研究，特别是可能产生新治疗方法的研究非常重要。在我们的初步研究中，在转基因和异种移植 PCa 小鼠模型中，选择性阻断免疫细胞中主要炎症转录因子 NF-κB 可显着损害去势抵抗性前列腺癌 (CR-PCa) 的发展。我们还发现，这种炎症反应的关键参与者之一是肿瘤浸润 B 细胞，它产生 LTa:¿刺激 LT 的异源三聚体¿ R在PCa细胞上诱导IKKa核转位和激活，从而增强雄激素非依赖性生长因此，我们建议定义LTs和LTs诱导的IKKa核转位和激活如何介导CR-PCa的形成，以及LTs表达的相关性。、IKKa 对人类前列腺癌的核定位和激活，我们相信我们的研究将为 B 细胞衍生的 LT 如何控制 CR-PCa 提供新的见解，并将为开发新的治疗策略奠定基础。激素难治性 PCa 的治疗和/或预防。公共健康相关性：拟议研究的目标是确定淋巴毒素（LT）介导的信号传导在控制雄激素非依赖性（AI）前列腺癌（PCa）的发展中的作用，PCa本质上是一种无法治愈的恶性肿瘤。采用最先进的遗传和分子方法，拟议的研究将为 LT 定向信号传导如何调节 AI PCa 形成提供新的见解，我们坚信这些研究将为开发新的治疗策略奠定基础用于治疗和/或预防激素难治性前列腺癌。