Interleukin-1beta and AR-negative tumor cells in metastatic castrate-resistant prostate cancer

转移性去势抵抗性前列腺癌中白介素 1β 和 AR 阴性肿瘤细胞

• 批准号: 10366584
• 负责人: Alessandro Fatatis
• 金额: $ 38.95万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366584
• 关键词: Adipocytes; Affect; Androgen Receptor; Androgens; Animal Model; Animals; Bypass; Cancer Patient; Cancer cell line; Castration; Cell Survival; Cells; Complement; Dinoprostone; Disease; Dose; Event; Excision; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Habitats; Habits; Harvest; Hormones; Human; Human Cell Line; Interleukin-1 beta; Knowledge; LNCaP; Lesion; Life Expectancy; Light; Long-Term Care; Malignant - descriptor; Malignant neoplasm of prostate; Mesalamine; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Metastatic to; MicroRNAs; Mixed Neoplasm; Modality; Modeling; Molecular; Molecular Biology; Mus; Neoplasm Metastasis; Osteoblasts; Osteoclasts; PC3 cell line; PTGS2 gene; Patients; Phenotype; Process; Prostate Cancer therapy; RANTES; Receptor Inhibition; Receptor Signaling; Regulation; Reporting; Resistance; Role; Structure; System; Testing; Testosterone; Therapeutic; Transcriptional Regulation; Tumor Tissue; Tumor-Derived; Up-Regulation; VCaP; advanced prostate cancer; androgen deprivation therapy; antagonist; autocrine; base; bone; cancer cell; castration resistant prostate cancer; celecoxib; cell stroma; chemokine; colonization resistance; cyclooxygenase 2; cytokine; deprivation; enzalutamide; experimental study; human tissue; improved; inhibitor; mesenchymal stromal cell; neoplastic cell; new therapeutic target; osteopontin; paracrine; patient derived xenograft model; pre-clinical; promoter; prostate cancer cell; receptor; receptor binding; receptor expression; receptor-mediated signaling; recruit; release factor; response; skeletal; targeted treatment; therapy outcome; tumor

Treatment of prostate cancer patients relies heavily on therapeutic strategies depriving tumor cells of the transcriptional activity of the Androgen Receptor (AR). Despite their initial efficacy, androgen-deprivation therapies (ADT) are eventually circumvented by the emergence of castrate-resistant prostate cancer (CRPC), which is characterized by skeletal metastases in more than 90% of patients. We have recently demonstrated that approximately 30% of bone-metastatic prostate cancer cells lack AR (ARNeg) and express Interleukin-1β (IL-1β). Our hypothesis is that ARNeg cancer cells, by secreting IL-1β, establish a supportive bone habitat, allows ARPos cells to withstand androgen-deprivation and AR inhibition. Thus, a major goal of this proposal is to define the modalities by which ARNeg/IL-1β cancer cells sustain skeletal colonization in prostate cancer under androgen-deprived conditions. This proposal is structured in three aims: Aim 1. IL-1β involvement in ADT resistance; Aim 2. Role of bone stroma in IL-1β induced regulation of ARPos cells; Aim 3. Regulation of IL-1β expression by AR. The proposed studies will employ animal models of metastasis, human cell lines, PDX-derived cells and human tissue amples to ascertain the functional role of IL-1β in skeletal colonization of prostate cancer cells, discriminating between direct autocrine-paracrine effects on cancer cells and targeting cells of the tumor- associated bone stroma. Furthermore, we will identify the bone stroma cells targeted by IL-1β and evaluate three stromal factors secreted in response to IL-1β for the ability to induce AR signaling and expression of AR- regulated genes. Finally, using a combination of molecular biology approaches we will define the mechanism for the transcriptional regulation of IL-1β by the AR and the translational control exerted on this cytokine by miRNAs. Our studies will define the unique role of ARNeg prostate cancer cells in metastases and provide conceptual and pre-clinical ground for complementary strategies to improve therapeutic outcomes.

前列腺癌患者的治疗在很大程度上依赖于剥夺肿瘤细胞的免疫原性的治疗策略。 雄激素受体（AR）的转录活性。尽管它们最初有效， 治疗（ADT）最终被去势抵抗性前列腺癌（CRPC）的出现所规避， 其特征在于超过90%的患者发生骨转移。 我们最近发现大约30%的骨转移性前列腺癌细胞缺乏AR （ARNeg）并表达白细胞介素-1 β（IL-1β）。我们的假设是ARNeg癌细胞通过分泌IL-1β， 建立支持性骨生境，允许ARPos细胞耐受雄激素剥夺和AR抑制。 因此，该提案的主要目标是确定ARNeg/IL-1β癌细胞维持免疫应答的方式。 在雄激素剥夺条件下前列腺癌的骨骼定殖。 该提案的结构分为三个目标：目标1。IL-1β参与ADT抵抗;目的2.骨的作用 IL-1β对ARPos细胞的调节作用;目的3. AR对IL-1β表达的调节。 所提出的研究将采用转移的动物模型、人细胞系、PDX衍生的细胞和肿瘤细胞。 人组织样本以确定IL-1β在前列腺癌细胞的骨骼定殖中的功能作用， 区分对癌细胞的直接自分泌-旁分泌效应和对肿瘤细胞的靶向效应- 相关的骨基质。此外，我们将鉴定IL-1β靶向的骨基质细胞，并评估 三种基质因子响应IL-1β分泌，能够诱导AR信号传导和AR表达， 调控基因最后，使用分子生物学方法的组合，我们将定义的机制 对于AR对IL-1β的转录调节以及AR对该细胞因子的翻译控制， miRNAs。 我们的研究将确定ARNeg前列腺癌细胞在转移中的独特作用，并提供概念和方法。 临床前基础的补充策略，以改善治疗效果。