Novel Mechanisms of ROS/RNS Signaling Underlying Castration-Resistant Prostate Cancer Emergence and Progression

去势抵抗性前列腺癌发生和进展的 ROS/RNS 信号传导新机制

基本信息

批准号：
10381045
负责人：
Priyamvada Rai
金额：
$ 7.7万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381045
关键词：
Agonist American Androgens Apoptosis Biological Process Biology CD44 gene Cancer Etiology Castration Cells Cessation of life Clinical Complex Cyclic GMP Data Data Set Disease FDA approved Failure Freezing Genetic Gold Growth Hormones Human Hypoxia In Vitro Laboratories Measures Metabolic Modeling Molecular Natural regeneration Outcome Oxidation-Reduction Oxides Pathway interactions Patients Periodicity Pharmaceutical Preparations Pharmacology Physiological Plasma Pre-Clinical Model Predictive Factor Radiation Research Resistance Serum Signal Transduction Soluble Guanylate Cyclase Specimen Stress Therapeutic Tissues Tumor Oxygenation Vasodilator Agents androgen deprivation therapy androgen sensitive bone castration resistant prostate cancer clinically actionable clinically relevant combinatorial deprivation efficacy testing in vivo men mouse model novel patient derived xenograft model pre-clinical prostate cancer cell prostate cancer model prostate cancer progression radiation resistance screening standard of care stem cell biomarkers stem cells subcutaneous therapeutic development therapeutically effective transcriptome transcriptomics tumor tumor hypoxia tumor xenograft

项目摘要

Abstract Limited understanding of molecular mechanisms underlying castration-resistant prostate cancer (CRPC)is a barrier to effective therapeutic development for this fatal disease. We identified the nitric oxide receptor complex, soluble guanylyl cyclase (sGC), as a novel CRPC-inhibitory target via unbiased transcriptomics screening of an emergent CRPC model developed in our lab. Analyses of human PC datasets and our preliminary results support that sGC activity is inhibited during CRPC progression from androgen-dependent PC, and that the sGC complex is oxidatively inactivated. However we find the redox-protective mechanisms induced by androgen deprivation (AD) to protect CRPC cells from apoptosis provides a therapeutic window during which sGC can be stimulated to maximal bioactivity. Thus, we hypothesize sGC activity inhibits CRPC growth and that its stimulation by clinically-approved agonists will be therapeutically beneficial in combination with standard-of-care AD. Our hypothesis is supported by our strong preclinical data showing that the FDA-approved vasodilator and sGC agonist, riociguat, reduces in vivo growth of castration-resistant xenograft tumors, decreases PSA and increases intratumoral cyclic cGMP, the product of sGC signaling and a measure of on- target riociguat efficacy. Consistent with its biological function, sGC stimulation induces robust tumor oxygenation as well as loss of the CD44 PC stem cell marker, suggesting that it destroys hypoxic stem cell niches. Castration resistance is associated with tumor hypoxia and consequent radioresistance. We find that riociguat increases the tumor-suppressive efficacy of radiation in CRPC xenograft tumors. Our objective is to comprehensively establish molecular mechanisms underlying how and why stimulating the sGC pathway limits CRPC growth and progression and to identify factors that predict anti-CRPC efficacy of sGC agonists in preclinical models. We will assess 1) how mechanisms that control sGC levels and molecular reducing partners that regenerate oxidized inactive sGC are altered in hormone-sensitive vs. castration-resistant cells, 2) how the physiologic effects of sGC bioactivity enact anti-CRPC outcomes, with consideration of hypoxia- associated PC- relevant metabolic and redox stress mechanisms, and 3) test the efficacy of sGC agonists in the spectrum of CRPC disease. Our in vitro studies will utilize robust preclinical models of emergence, growth, progression and metastatic colonization of the bone milieu. We will utilize genetic and pharmacologic means to modulate sGC expression and activity in gold standard culture models that recapitulate the relevant clinical features of CRPC and we will utilize robust subcutaneous, orthotopic and metastatic preclinical mouse models as well as patient-derived xenografts (PDXs). We will validate key molecular findings in de-identified PC patient-derived specimens including fixed and frozen tissue, serum, and plasma. Our studies will uncover novel biology underlying CRPC growth and progression, and potentially provide preclinical rationale for re-purposing sGC agonists in combinatorial treatments with standard-of-care AD.

抽象的对去势抵抗性前列腺癌 (CRPC) 分子机制的了解有限阻碍这种致命疾病的有效治疗发展。我们鉴定出一氧化氮受体复杂的可溶性鸟苷酸环化酶（sGC），通过无偏转录组学作为新型 CRPC 抑制靶点筛选我们实验室开发的新兴 CRPC 模型。人类 PC 数据集的分析和我们的初步结果支持 sGC 活性在雄激素依赖性 PC 进展为 CRPC 期间受到抑制，并且 sGC 复合物被氧化失活。然而我们发现氧化还原保护机制诱导通过雄激素剥夺（AD）保护CRPC细胞免于凋亡提供了一个治疗窗口，在此期间 sGC 可以被刺激到最大的生物活性。因此，我们假设 sGC 活性抑制 CRPC 生长并且临床批准的激动剂的刺激将在治疗上有益于与标准护理 AD。我们的假设得到了强有力的临床前数据的支持，这些数据表明 FDA 批准的血管扩张剂和 sGC 激动剂利奥西呱可减少去势抵抗性异种移植肿瘤的体内生长，降低 PSA 并增加瘤内环化 cGMP，这是 sGC 信号传导的产物，也是一种测量目标利奥西呱疗效。与其生物学功能一致，sGC 刺激可诱导强健的肿瘤氧合以及 CD44 PC 干细胞标记物的丢失，表明它会破坏缺氧干细胞利基市场。去势抵抗与肿瘤缺氧和随之而来的放射抵抗有关。我们发现利奥西呱可提高放疗对 CRPC 异种移植肿瘤的肿瘤抑制功效。我们的目标是全面建立如何以及为何刺激 sGC 通路限制的分子机制 CRPC 的生长和进展，并确定预测 sGC 激动剂抗 CRPC 功效的因素临床前模型。我们将评估 1) 如何控制 sGC 水平和分子减少的机制激素敏感细胞与去势抵抗细胞中再生氧化非活性 sGC 的伙伴发生了改变， 2) 考虑到缺氧，sGC生物活性的生理效应如何产生抗CRPC结果相关的 PC 相关代谢和氧化还原应激机制，以及 3) 测试 sGC 激动剂在 CRPC 疾病谱。我们的体外研究将利用强大的临床前模型，包括出现、生长、骨环境的进展和转移定植。我们将利用遗传和药理学手段调节黄金标准培养模型中的 sGC 表达和活性，重现相关临床 CRPC 的特点，我们将利用强大的皮下、原位和转移性临床前小鼠模型以及患者来源的异种移植物（PDX）。我们将验证去识别 PC 中的关键分子发现患者来源的样本，包括固定和冷冻的组织、血清和血浆。我们的研究将发现新颖的 CRPC 生长和进展的生物学基础，并可能为重新利用提供临床前理由 sGC 激动剂与标准护理 AD 的组合治疗。