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

• 批准号: 10212358
• 负责人: Priyamvada Rai
• 金额: $ 35.11万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212358
• 关键词: Affect; Agonist; American; Androgen Receptor; Androgens; Antitumor Response; Automobile Driving; Biological Assay; Biology; CD44 gene; Cancer Etiology; Cardiopulmonary; Castration; Cells; Cessation of life; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cyclic GMP; DNA; DNA Repair; Data; Data Set; Development; Disease; Down-Regulation; FDA approved; Failure; Genetic; Genetic Transcription; Growth; Heme; Hormones; Hypoxia; Kinetics; Laboratories; Maintenance; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Natural regeneration; Neoplasm Metastasis; Oncogenic; Outcome; Oxidation-Reduction; Oxidative Stress; Oxides; PSA level; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Proteins; Pulmonary Hypertension; Radiation; Reactive Oxygen Species; Reagent; Refractory; Regulation; Research; Resistance; Respiration; Signal Pathway; Signal Transduction; Soluble Guanylate Cyclase; Specimen; Stress; Testing; Therapeutic; Translations; Treatment Efficacy; Tumor Oxygenation; Vasodilator Agents; Xenograft Model; Xenograft procedure; androgen deprivation therapy; base; bone; cancer stem cell; castration resistant prostate cancer; clinical translation; clinically actionable; clinically relevant; combat; combinatorial; deprivation; hypertension treatment; improved; in vivo; men; novel; overexpression; patient derived xenograft model; patient stratification; potential biomarker; pre-clinical; prevent; progression marker; prostate cancer model; response; screening; small hairpin RNA; standard of care; stem; stem cell biomarkers; stem cell population; stem cells; transcriptome; transcriptomics; tumor; tumor growth; tumor hypoxia

Abstract Castration-resistant prostate cancer (CRPC), a fatal disease, remains therapeutically underserved due to limited understanding of molecular factors underlying its emergence and progression. Through unbiased transcriptomics analysis of an early CRPC model developed in our lab and patient dataset analyses, we have discovered that stimulation of the nitric oxide receptor complex, soluble guanylate cyclase (sGC), in conjunction with standard-of-care androgen deprivation (AD) is likely to be therapeutically beneficial in CRPC. Based on our preliminary results, our hypothesis is that decreased sGC activity promotes CRPC growth and that increasing sGC activity will limit CRPC emergence and progression. The rationale of our studies, supported by our findings and well-characterized sGC regulatory mechanisms from the cardiopulmonary field, is that sGC is oxidized and refractory to stimulation in CRPC but is functionally regenerated by AD-induced redox-protective responses. Thus, the combinatorial use of sGC agonists and AD is predicted to be an effective strategy to combat CRPC. The sGC agonist, riociguat, is FDA-approved as a vasodilator in pulmonary hypertension treatment. Our preliminary data show riociguat reduces xenograft CRPC growth. This anti-tumor response is accompanied by lowered PSA levels as well as increased systemic and intratumoral cyclic GMP (cGMP) levels, indicating on- target stimulation of sGC bioactivity. Consistent with the physiologic function of enhanced sGC activity, we find riociguat treatment leads to marked tumor oxygenation and decreased levels of CD44, a key PC stem cell marker. Thus, riociguat efficacy may derive from eradication of hypoxic niches and the residing androgen- refractory stem cell populations thought to underlie CRPC. Hypoxia also alters the tumor redox state through mitochondrially-generated ROS that regulate angiogenic signaling. Through its putative targeting of cancer stem cells and redox vulnerabilities, riociguat is novel in PC therapy, and is safe and well-tolerated longterm. Our objective is to comprehensively establish mechanisms underlying how and why stimulating the sGC pathway limits CRPC growth and progression. Therefore, in these studies, we will assess 1) how mechanisms that control sGC expression and regenerate oxidized inactive sGC are altered in hormone-sensitive vs. castration-resistant cells, 2) how enhancement of sGC bioactivity induces anti-CRPC outcomes through consideration of hypoxia- associated metabolic and redox stresses, including those induced by androgen receptor re-activation under AD, and 3) test riociguat efficacy in the spectrum of CRPC disease, using robust preclinical and patient-derived models encompassing emergence, growth, progression and metastatic bone colonization. We will validate key molecular findings in de-identified PC patient specimens. Our studies possess strong potential to uncover novel mechanisms underlying PC progression, and for clinical translation via repurposing riociguat to treat CRPC.

抽象的 持续性前列腺癌（CRPC）是一种致命的疾病 有限地了解其出现和进展的分子因素。通过公正 在我们的实验室和患者数据集分析中开发的早期CRPC模型的转录组学分析，我们有 发现刺激一氧化氮受体复合物，可溶性鸟苷酸环化酶（SGC） 随着护理标准的雄激素剥夺（AD），在CRPC中可能在治疗上有益。基于我们 初步结果，我们的假设是SGC活性降低会促进CRPC的增长，并增加 SGC活性将限制CRPC的出现和进展。我们的研究的基本原理，得到我们的发现的支持 来自心肺场的特征良好的SGC调节机制是SGC已被氧化，并且 对CRPC刺激的难治性，但在功能上通过AD诱导的氧化还原保护反应再生。 因此，预测SGC激动剂和AD的组合使用是对抗CRPC的有效策略。 SGC激动剂Riociguat被FDA批准为肺动脉高压治疗中的血管扩张剂。我们的 初步数据显示，riociguat降低了异种移植CRPC的生长。这种抗肿瘤反应伴随着 PSA水平降低以及增加的全身性和肿瘤内环状GMP（CGMP）水平，表明现有 SGC生物活性的目标刺激。与增强的SGC活性的生理功能一致，我们发现 riociguat治疗导致明显的肿瘤氧合和CD44的水平降低，这是一个关键的PC干细胞 标记。因此，riociguat疗效可能来自根除低氧壁ch和居住的雄激素 - 难治性干细胞群体被认为是CRPC的基础。缺氧还通过 线粒体生成的ROS，调节血管生成信号传导。通过推定的癌症靶向 细胞和氧化还原脆弱性，riociguat在PC治疗中是新颖的，长期安全且耐受性良好。我们的 目的是全面建立如何以及为什么刺激SGC途径的机制 限制CRPC的增长和进展。因此，在这些研究中，我们将评估1）如何控制机制 SGC表达和再生氧化的非活性SGC在激素敏感与castration抗性中改变了 细胞，2）SGC生物活性的增强如何通过考虑缺氧 - 相关的代谢和氧化还原应激，包括AD下雄激素受体重新激活引起的胁迫， 3）使用可靠的临床前和患者衍生 模型包括出现，生长，进展和转移性骨定殖。我们将验证密钥 去识别的PC患者标本中的分子发现。我们的研究具有很大的揭示新颖的潜力 PC进展的基础机制，以及通过重新利用riociguat治疗CRPC的临床翻译。