Early clinial trials for Angelica herbal supplements for prostate cancer interception

当归草药补充剂拦截前列腺癌的早期临床试验

基本信息

批准号：
10366646
负责人：
Monika Joshi
金额：
$ 62.33万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366646
关键词：
Acetates Acute Address Adverse effects Androgen Receptor Androgens Anemia Angelica Angelica Root Animal Cancer Model Animal Model Animals Area Under Curve Behavior Biochemical Biological Availability Biological Markers Blood Cancer Burden Cancer Patient Cannabis Caring Castration Cells Chronic Clinic Clinical Cytochrome P450 DNA Repair Data Decision Making Disease Disease Progression Dose Drug Kinetics Drug Targeting FDA approved Face Failure Fatigue Fish Oils Food Food Interactions Fracture Frequencies Future Goals Gynecomastia Half-Life Health Herbal supplement Hot flushes Human IL8 gene Immune Immunologic Markers Immunologic Surveillance Immunophenotyping Immunosuppression Impotence Inflammation Inflammatory Intercept Knowledge Koreans Malignant Neoplasms Malignant neoplasm of prostate Measures Medical Castration Memory Memory Loss Messenger RNA Metabolic Microtubules Modality Mus Natural Increases Nature Oncology Oral Osteoporosis Outcome PSA level Pain Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacogenetics Phase Phase I Clinical Trials Phase I/II Trial Plant Roots Plasma Prevention Prevention therapy Prostate Prostate Cancer therapy Prostate-Specific Antigen Publishing Radiation therapy Radical Prostatectomy Randomized Controlled Trials Raspberries Recurrence Recurrent Malignant Neoplasm Reporting Rodent Safety Secondary Prevention Secondary to Sexual Dysfunction Signal Transduction Tea Testing Therapeutic Time Tissues Toxic effect abiraterone androgen deprivation therapy anti-cancer base chemokine cohort curative treatments cytokine design disorder prevention dosage efficacy outcomes enzalutamide genetic signature human study human subject in vivo inhibitor lean body mass mortality novel patient population pharmacodynamic biomarker prevent problem drinker prostate cancer model receptor response safety outcomes side effect soy taxane

项目摘要

PROJECT SUMMARY The slow growing nature of most prostate cancers (PCa) provides multiple windows of opportunity to block or delay disease progression to significantly reduce patient suffering and mortality. This is especially true following the failure of radical prostatectomy (RP) and radiation therapy (RT) of PCa prior to androgen deprivation therapy (ADT; i.e., medical or surgical castration). Biochemical recurrent PCa is sensitively indicated by rising blood prostate specific antigen (PSA). ADT is not curative and causes many serious adverse effects. Our goal is to develop Angelica gigas Nakai (AGN, Korean Angelica) root ethanolic extract or its constituent(s) as a safer and practical modality for PCa interception akin to secondary prevention to delay ADT or avoid it entirely. We hypothesize that (1) the PCa interception efficacy of AGN and its pyranocoumarins in animal models is extendable into human PCa patients, given sufficient AGN dosage and exposure duration; (2) multiple mechanisms including immune surveillance and suppression of inflammation contribute to the clinical cancer interception activity. The scientific premise is based on the presence of novel active pyranocoumarin compounds distinct from those in soy, tea, fish oil, raspberries, mushrooms, and cannabis and reported broad spectrum anti- cancer efficacy in animal cancer models. Moreover, we have demonstrated a) Oral bioavailability and favorable pharmacokinetic (PK) metrics in rodents and in humans; b) Cytochrome P450 (CYP) 2C19 and 3A4 first-pass conversion of pyranocoumarins decursin (D) and decursinol angelate (DA) to their metabolite decursinol (DOH); c) Proficient tissue retention of decursinol in mouse target prostate; d) Animal modeling of AGN and decursinol showing independence of the androgen receptor axis, avoiding side effects of ADT drugs and making blood PSA a reliable readout for cancer burden; e) AGN enhanced immune and decreased inflammatory gene signatures in an animal PCa model; and f) A single AGN dose in human subjects increased natural killer [NK] mRNA signature and decreased IL-8 chemokine mRNA in their peripheral blood mononuclear cells. We propose 3 specific aims in post-RP and post-RT patients with rising plasma PSA that is “clean” (due to prostate already removed) and indicative of the biochemical recurrent PCa burden. Aim 1. Characterize pyranocoumarin PK dose response proportionality to AGN supplement and food effects in 12 patients to probe any metabolic ceiling and minimize food-herbal interaction. Aim 2. Evaluate safety and recurrent PCa (PSA)-interception efficacy of twice daily AGN supplement in a Phase I/II trial with 36 patients. Aim 3. Measure acute- and repeated-dose PK metrics, CYP 2C19 and 3A4 metabolizer status and changes of immune and inflammation biomarkers to correlate to PSA outcomes. Impacts: The safety information and a favorable PSA response will guide future randomized control trials to prevent or treat PCa and other cancers. The novel knowledge on PK dose response, repeated dose PK behavior, CYP pharmacogenetics and the immune biomarkers not only fills in critical gaps for AGN supplements in cancer patients, but also is exportable to disease prevention and therapy beyond oncology.

项目概要大多数前列腺癌 (PCa) 生长缓慢的特性提供了多个阻断或治疗的机会窗口延缓疾病进展，显着减少患者的痛苦和死亡率，这一点尤其如此。雄激素剥夺治疗前前列腺癌根治性切除术 (RP) 和放射治疗 (RT) 失败（ADT；即药物或手术去势）生化复发性 PCa 可由血液升高敏感地指示。前列腺特异性抗原 (PSA) 没有治疗作用，并且会导致许多严重的副作用。开发当归（AGN，韩国当归）根乙醇提取物或其成分，作为一种更安全、更安全的产品 PCa 拦截的实用方式类似于二级预防，以延迟或完全避免 ADT。研究发现 (1) AGN 及其吡喃香豆素在动物模型中的 PCa 拦截功效为给予足够的 AGN 剂量和暴露时间 (2) 倍，可扩展到人类 PCa 患者；包括免疫监视和抑制炎症在内的机制有助于临床癌症拦截活性的科学前提是基于新型活性吡喃香豆素化合物的存在。与大豆、茶、鱼油、覆盆子、蘑菇和大麻中的成分不同，据报道具有广谱抗- 此外，我们还证明了 a) 口服生物利用度和良好的抗癌功效。 b) 细胞色素 P450 (CYP) 2C19 和 3A4 首次通过的药代动力学 (PK) 指标；将吡喃香豆素类地花素 (D) 和地花素当归酸酯 (DA) 转化为其代谢物地花素醇 (DOH)； c) decursinol 在小鼠靶前列腺中的有效组织保留 d) AGN 和 decursinol 的动物模型；显示雄激素受体轴的独立性，避免 ADT 药物的副作用并提高血液 PSA 可靠的癌症负担读数；e) AGN 增强免疫并减少炎症基因特征；在动物 PCa 模型中；和 f) 人类受试者中的单次 AGN 剂量增加了自然杀伤 [NK] mRNA 我们提出了 3 个特征并减少了外周血单核细胞中的 IL-8 趋化因子 mRNA。 RP 后和 RT 后血浆 PSA 升高的患者的具体目标是“干净的”（因为前列腺已经目的 1. 表征吡喃香豆素 PK 剂量。 12 名患者对 AGN 补充剂和食物影响的反应比例，以探究任何代谢上限和目标 2. 评估安全性和复发 PCa (PSA) 拦截功效两倍。在 36 名患者参与的 I/II 期试验中每日补充 AGN。目标 3. 测量急性和重复剂量 PK 指标， CYP 2C19 和 3A4 代谢状态以及与 PSA 相关的免疫和炎症生物标志物的变化结果：安全性信息和有利的 PSA 反应将指导未来的随机对照。预防或治疗 PCa 和其他癌症的试验关于 PK 剂量反应、重复剂量 PK 的新知识。行为、CYP 药物遗传学和免疫生物标志物不仅填补了 AGN 补充剂的关键空白不仅适用于癌症患者，而且还可以应用于肿瘤学以外的疾病预防和治疗。