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：
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
项目类别：
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

项目摘要

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.

抽象的去势抵抗性前列腺癌 (CRPC) 是一种致命疾病，但由于对其出现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 模型进行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物、可溶性鸟苷酸环化酶（sGC）的刺激，与采用标准护理雄激素剥夺 (AD) 可能对 CRPC 具有治疗效果。基于我们的初步结果显示，我们的假设是 sGC 活性的降低会促进 CRPC 的生长，而 sGC 活性的增加会促进 CRPC 的生长。 sGC 活性将限制 CRPC 的出现和进展。我们研究的基本原理，得到我们的研究结果的支持心肺领域已充分表征的 sGC 调节机制是 sGC 被氧化并 CRPC 中的刺激难以抵抗，但可通过 AD 诱导的氧化还原保护反应进行功能再生。因此，sGC激动剂和AD的联合使用预计将是对抗CRPC的有效策略。 sGC 激动剂利奥西呱 (riociguat) 已获得 FDA 批准作为肺动脉高压治疗的血管扩张剂。我们的初步数据显示利奥西呱可减少异种移植 CRPC 的生长。这种抗肿瘤反应伴随着 PSA 水平降低，全身和瘤内环鸟苷酸 (cGMP) 水平升高，表明 sGC 生物活性的目标刺激。与增强 sGC 活性的生理功能一致，我们发现利奥西呱治疗导致显着的肿瘤氧合和 CD44（一种关键的 PC 干细胞）水平降低标记。因此，利奥西呱的功效可能来自于根除缺氧生态位和残留的雄激素。难治性干细胞群被认为是 CRPC 的基础。缺氧还通过以下方式改变肿瘤氧化还原状态线粒体产生的 ROS 调节血管生成信号。通过其假定的癌症干细胞靶向利奥西呱在 PC 治疗中是新颖的，并且安全且长期耐受性良好。我们的目标是全面建立如何以及为何刺激 sGC 通路的机制限制 CRPC 的生长和进展。因此，在这些研究中，我们将评估 1）控制机制如何激素敏感型与去势抵抗型的 sGC 表达和再生氧化非活性 sGC 发生变化细胞，2) sGC 生物活性的增强如何通过考虑缺氧诱导抗 CRPC 结果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应激， 3) 使用可靠的临床前和患者来源的数据来测试利奥西呱对 CRPC 疾病谱的疗效涵盖出现、生长、进展和转移性骨定植的模型。我们将验证密钥未识别的 PC 患者标本中的分子发现。我们的研究具有发现新奇事物的强大潜力 PC 进展的机制，以及通过重新利用利奥西呱治疗 CRPC 进行临床转化。