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

基本信息

批准号：
10686804
负责人：
Alessandro Fatatis
金额：
$ 38.17万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
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/10686804
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 Harvest Hormones Human Human Cell Line IL1R1 gene Interleukin-1 beta Knowledge LNCaP Lesion Life Expectancy Long-Term Care Malignant - descriptor Malignant neoplasm of prostate Mesalamine Metastatic Neoplasm to the Bone Metastatic Prostate Cancer MicroRNAs Mixed Neoplasm Modality Modeling Molecular Molecular Biology Mus Neoplasm Metastasis Osteoblasts Osteoclasts PC3 cell line 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 bone cancer cell castration resistant prostate cancer celecoxib cell stroma chemokine cyclooxygenase 2 cytokine deprivation derepression enzalutamide experimental study gene repression 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

项目摘要

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.

癌症患者的治疗在很大程度上依赖于剥夺肿瘤细胞的治疗策略雄激素受体（AR）的转录活性尽管最初有效，但雄激素剥夺。治疗（ADT）最终因去势抵抗性前列腺癌（CRPC）的出现而被规避，其特点是90%以上的患者出现骨骼转移。我们最近证明，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-1β (IL-1β)。我们的假设是 ARNeg 癌细胞通过分泌 IL-1β，建立支持性骨骼栖息地，使 ARPos 细胞能够承受雄激素剥夺和 AR 抑制。因此，该提案的一个主要目标是确定 ARNeg/IL-1β 癌细胞维持生存的方式雄激素剥夺条件下前列腺癌的骨骼定植。该提案分为三个目标：目标 1. IL-1β 参与 ADT 抵抗；目标 2. 骨的作用； IL-1β 中的基质诱导 ARPos 细胞的调节；目标 3. AR 对 IL-1β 表达的调节。拟议的研究将采用转移动物模型、人类细胞系、PDX 衍生细胞和人体组织样本以确定 IL-1β 在前列腺癌细胞骨骼定植中的功能作用，区分对癌细胞的直接自分泌-旁分泌作用和肿瘤的靶向细胞此外，我们将鉴定 IL-1β 靶向的骨基质细胞并进行评估。响应 IL-1β 分泌的三种基质因子能够诱导 AR 信号传导和 AR-表达最后，我们将结合分子生物学方法来定义其机制。 AR 对 IL-1β 的转录调节以及对这种细胞因子的翻译控制 miRNA。我们的研究将定义 ARNeg 前列腺癌细胞在转移中的独特作用，并提供概念和理论依据。为改善治疗结果的补充策略提供临床前基础。