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.

摘要 抗去势前列腺癌(CRPC)是一种致命的疾病，目前仍未得到足够的治疗 对其发生和发展背后的分子因素的了解有限。通过不偏不倚 对我们实验室开发的早期CRPC模型的转录组学分析和患者数据集分析，我们有 发现一氧化氮受体复合体--可溶性鸟苷环化酶(SGC)的刺激与 在标准护理下，雄激素剥夺(AD)在CRPC的治疗上可能是有益的。基于我们的 初步结果，我们的假设是sGC活性降低促进CRPC生长，而增加 SGC活性将限制CRPC的出现和进展。我们研究的基本原理，得到了我们的发现的支持 而来自心肺领域的sGC调节机制的特征是sGC被氧化并 CRPC对刺激不敏感，但可通过AD诱导的氧化还原保护反应在功能上再生。 因此，sGC激动剂和AD的联合应用有望成为对抗CRPC的有效策略。 SGC激动剂riociguat是FDA批准的用于治疗肺动脉高压的血管扩张剂。我们的 初步数据显示，Riociguat减少了异种移植CRPC的生长。这种抗肿瘤反应伴随着 PSA水平下降以及全身和肿瘤内循环GMP(CGMP)水平上升，表明- 靶向刺激sGC生物活性。与sGC活性增强的生理功能一致，我们发现 利奥昔格特治疗导致显著的肿瘤氧合和关键的PC干细胞CD44水平下降 记号笔。因此，Riociguat的疗效可能来自于根除低氧生态位和残留的雄激素- 难治性干细胞群体被认为是CRPC的基础。缺氧还通过以下途径改变肿瘤的氧化还原状态 线粒体产生的ROS调节血管生成信号。通过其假定的靶向癌症干细胞 在细胞和氧化还原脆弱性方面，Riociguat在PC治疗中是新的，并且是安全的和长期耐受性良好的。我们的 目标是全面建立如何以及为什么刺激sGC途径的机制 限制了CRPC的发展和进步。因此，在这些研究中，我们将评估1)控制 激素敏感型与去势抗性相比，SGC表达和再生氧化失活的SGC发生改变 细胞，2)sGC生物活性的增强如何通过考虑缺氧而诱导抗CRPC结果- 相关的代谢和氧化还原压力，包括在AD下雄激素受体重新激活所引起的压力， 3)使用强大的临床前和患者来源，在CRPC病谱中测试利奥昔格特的疗效 包括出现、生长、进展和转移性骨定植的模型。我们将验证密钥 未鉴定的前列腺癌患者标本中的分子表现。我们的研究具有很强的发现小说的潜力 PC进展的潜在机制，以及通过改变利奥瓜特的用途来治疗CRPC的临床翻译。