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。

• 批准号: 8042328
• 负责人: Jun-Li Luo
• 金额: $ 43.02万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/8042328
• 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; Clinical; Collaborations; Consumption; Cooperative Human Tissue Network; Dendritic Cells; Development; Disease; Epidemiologic Studies; Epithelial Cells; Evolution; Foundations; Genetic Transcription; Genotype; Goals; Growth; 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

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发展为局部浸润性腺癌，然后发展为难治性癌。 对于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。 然而，对于难治性前列腺癌，没有有效的治疗方法。 雄激素剥夺治疗（ADT）是晚期PCa的初始全身治疗，并用作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，对激素难治性前列腺癌形成机制的研究，特别是可能导致新的治疗方法的研究，是非常重要的。 在我们的初步研究中，选择性阻断NF-？免疫细胞中的主要炎性转录因子B在转基因和异种移植PCa小鼠模型中显著地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性B细胞，它产生LTa：异源三聚体，刺激PCa细胞上的LT R，诱导IKKa核转位和活化，从而增强雄激素非依赖性生长。 因此，我们建议定义LT和LT诱导的IKKa核转位和激活如何介导CR-PCa的形成，以及LT表达，IKKa核定位和激活与人前列腺癌的相关性。 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，并将为开发治疗和/或预防激素难治性PCa的新治疗策略奠定基础。 公共卫生关系：拟议研究的目标是确定光氧（LT）导向信号在控制雄激素非依赖性（AI）前列腺癌（PCa）发展中的作用，这基本上是一种无法治愈的恶性肿瘤。 使用最先进的遗传和分子方法，拟议的研究将为LT指导的信号传导如何调节AI PCa形成提供新的见解，我们坚信这些研究将为开发治疗和/或预防激素难治性前列腺癌的新治疗策略奠定基础。