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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.

摘要