Androgen Activation of Innate Immune Signaling to Enhance Prostate Cancer Immune Response

雄激素激活先天免疫信号以增强前列腺癌免疫反应

基本信息

批准号：
10532225
负责人：
Samuel R Denmeade
金额：
$ 48.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10532225
关键词：
Adaptive Immune System Agonist Androgen Analogues Androgen Receptor Androgen Therapy Androgens Apoptosis Autophagocytosis Autophagosome Biopsy CRISPR/Cas technology Cancer Biology Cancer Patient Castration Cell model Cells Chronic Clinical Clinical Management Clinical Research Cytoplasm DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Gene Data Defect Disease Dose Environment Exposure to FDA approved Gene Amplification Genes Goals Growth Hormonal Hormones Hour Human Immune Immune response Immune signaling Immunotherapeutic agent In Vitro Infiltration Injections Innate Immune System Interferons Knock-out Left Ligands Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Mutation NF-kappa B Nature Nucleic Acids PSA level Pain Pathway interactions Patients Positioning Attribute Prediction of Response to Therapy Process Production Prostatic Neoplasms Quality of life Receptor Signaling Recurrence Resistance Resolution Resources Role Serum Sex Functioning Signal Transduction Stimulator of Interferon Genes TP53 gene Testing Testosterone Therapeutic Treatment Efficacy Variant Work Xenograft Model Xenograft procedure advanced prostate cancer androgen deprivation therapy antitumor effect biomarker development cancer immunotherapy castration resistant prostate cancer chemokine digital ds-DNA empowerment exposed human population genetic signature humanized mouse immune activation immune checkpoint blockade immunoregulation improved in vivo innate immune pathways innovation insight men mouse model novel overexpression pain relief palliative patient subsets pre-clinical preclinical study prostate biopsy prostate cancer cell prostate cancer cell line response sensor synergism tool translational approach treatment duration treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

Bipolar androgen therapy (BAT) is a paradoxical approach for the treatment of castration-resistant prostate cancer (CRPC) whereby testosterone levels are rapidly cycled between supraphysiologic and castrate concentrations. Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. Previous observations suggest that supraphysiological testosterone (SupraT) induce DNA double strand breaks (DSB). It has been speculated that if left unrepaired, DSBs may lead to cellular crisis and apoptosis. In this proposal, we provide novel evidence that unrepaired DSBs induced by SupraTs are routed to the autophagosomes where they activate cytoplasmic nucleic acid sensors that trigger the downstream interferon stimulated genes (ISGs) and innate immune pathways. Based on our preliminary data, we propose a novel idea that: i) Unrepaired DSBs induced by SupraTs are routed for specialized autophagic degradation termed nucleophagy; ii) SupraTs induced autophagosomal DNA can activate cytoplasmic DNA sensing pathways~ specifically the nucleic acid sensing pathway (cGAS-STING and RIG-I pathway); iii) Activation of nucleic acid sensing pathway by SupraTs would be more pronounced in prostate tumors that have DNA repair defect; and iv) BAT might activate innate and adaptive immune cells specially, in a subset of patients having DNA repair defect. In this proposal, we will determine the role of nucleic acid sensors in mediating immune signaling by SupraTs in PCa. Utilizing tumor biopsies from PCa patients receiving BAT, we will evaluate whether nucleic acid sensor mediated innate immune signaling serves as a molecular determinant of treatment response. To test our hypothesis, we will utilize several innovative tools and resources including CRISPR-Cas9 generated knockout cellular models, GeoMx Digital Spatial profiling of immune landscape in the tumor microenvironment, unique patient derived prostate cancer xenografts models, a humanized mouse models that has functional innate and adaptive immune cells, and serum and tumor biopsies from patients receiving BAT. We think these unique resources position us well to undertake the proposed work with immediate clinical impact. We have assembled a team of experts in basic and clinical prostate cancer biology and immunotherapy who will provide their unique expertise to successfully accomplish our goals. Successful completion of the proposed work will generate: a) mechanistic insights into modulation of immune response by SupraTs, b) valuable clinical insights into activation of immune cells by BAT, c) novel tumor- and serum-based markers that can be utilized for the development of biomarkers predictive of therapy response, and d) provide a rationale for strategically utilizing BAT to activate immune response and combine it with immunotherapeutics that empower the adaptive immune system such as immune checkpoint blockade and T-cell therapeutics to achieve synergy.

双极雄激素疗法（BAT）是治疗castration抗性前列腺癌的一种自相矛盾的方法（CRPC）睾丸激素水平迅速循环在造型生理学和castrate浓度之间。了解蝙蝠在分子和细胞水平上的工作方式可能有助于合理地将BAT与其他药物可以提高功效和肿瘤反应。以前的观察表明上造式生理睾丸激素（Suprat）诱导DNA双链断裂（DSB）。有人推测，如果剩下未修复的DSB可能导致细胞危机和凋亡。在此提案中，我们提供了新的证据 Suprats诱导的未修复的DSB被路由到自噬体激活细胞质核酸触发下游干扰素刺激基因（ISG）和先天免疫途径的酸传感器。基于在我们的初步数据上，我们提出了一个新颖的想法：i）Suprats引起的未修复的DSB被路由专门的自噬降解称为亲核； ii）Suprats诱导的自噬体DNA可以激活细胞质DNA传感途径〜特别是核酸传感途径（CGAS和RIG-I 途径）; iii）在前列腺肿瘤中激活核酸传感途径会更明显具有DNA修复缺陷； iv）蝙蝠可能会在一部分中特别激活先天和适应性免疫细胞患有DNA修复缺陷的患者。在此提案中，我们将确定核酸传感器在介导中的作用 Suprats在PCA中的免疫信号传导。利用接受蝙蝠的PCA患者的肿瘤活检，我们将评估核酸传感器介导的先天免疫信号传导是否是治疗的分子决定因素回复。为了检验我们的假设，我们将利用几种包括CRISPR-CAS9在内的创新工具和资源产生的基因敲除蜂窝模型，肿瘤中免疫景观的GEOMX数字空间分析微环境，独特的患者衍生的前列腺癌异种移植模型，一种具有人源的小鼠模型，具有功能性先天和适应性免疫细胞，以及接受BAT的患者的血清和肿瘤活检。我们认为这些独特的资源将我们良好地定位，以立即临床影响进行拟议的工作。我们有组建了一个基本和临床前列腺癌生物学和免疫疗法的专家团队，他们将提供他们的独特的专业知识可以成功实现我们的目标。成功完成拟议的工作将产生： a）Suprats对免疫反应调节的机理洞察力，b）对激活的宝贵临床见解通过BAT，c）可用于开发的新型肿瘤和血清基标记物的免疫细胞预测治疗反应的生物标志物，d）为从策略上利用蝙蝠激活提供了理由免疫反应并将其与免疫治疗剂结合使用，以赋予适应性免疫系统的能力，例如免疫检查点封锁和T细胞疗法以实现协同作用。