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.

抽象的对耐castration-抗性前列腺癌（CRPC）的分子机制的了解有限这种致命疾病有效治疗发育的障碍。我们确定了一氧化氮受体复杂的，可溶性的鸟叶酸环化酶（SGC），通过无偏的转录组学作为新型CRPC抑制靶标筛选我们实验室中开发的紧急CRPC模型。分析人类PC数据集和我们的初步结果支持SGC活性在CRPC进展过程中受到雄激素依赖性PC的抑制。 SGC复合物被氧化灭活。但是，我们发现氧化还原保护机制诱导了通过雄激素剥夺（AD）保护CRPC细胞免受凋亡的侵蚀，提供了一个治疗窗口，在此期间 SGC可以刺激以最大生物活性。因此，我们假设SGC活性抑制了CRPC的增长和它被临床批准的激动剂刺激将在治疗上与护理标准广告。我们的强大临床前数据证明了我们的假设，表明FDA批准了血管扩张剂和SGC激动剂，riociguat，减少了耐castration耐药异种移植肿瘤的体内生长降低PSA并增加肿瘤内环状CGMP，SGC信号的乘积和量度目标riociguat功效。与其生物学功能一致，SGC刺激会诱导健壮的肿瘤 CD44 PC干细胞标记物的氧合以及损失，表明它会破坏低氧干细胞利基。 cast割耐药性与肿瘤缺氧和随之而来的放射性相关。我们发现 riociguat增加了CRPC异种移植肿瘤辐射的肿瘤抑制功效。我们的目标是全面建立如何以及为何刺激SGC途径限制的分子机制 CRPC的增长和进展，并确定可以预测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水平和分子降低的机制在激素敏感与castration抗性细胞中，再生氧化无活性SGC的伴侣改变了 2）SGC生物活性的生理影响如何产生抗CRPC结果，并考虑到缺氧 - 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疾病的频谱。我们的体外研究将利用强大的出现临床前模型，生长，骨环境的进展和转移定殖。我们将利用遗传和药理手段在黄金标准培养模型中调节SGC表达和活性，这些模型概括了相关的临床 CRPC的功能，我们将利用强大的皮下，原位和转移性临床前鼠标模型以及患者衍生的异种移植物（PDXS）。我们将验证取消识别的PC中的关键分子发现患者衍生的标本，包括固定组织和冷冻组织，血清和血浆。我们的研究将发现小说 CRPC生长和进步的生物学，并有可能提供临床前原理以重新定位 SGC激动剂在组合处理标准AD中。