Early clinial trials for Angelica herbal supplements for prostate cancer interception

项目摘要 大多数前列腺癌（PCa）生长缓慢的性质提供了多个机会窗口来阻止或 延缓疾病进展，显著降低患者痛苦和死亡率。这是特别真实的以下 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，内科或外科阉割）。生化复发性前列腺癌敏感地提示血液升高 前列腺特异性抗原（PSA）。ADT不是治愈性的，并导致许多严重的不良反应。我们的目标是 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和 PCa拦截的实用模式类似于二级预防，以延迟ADT或完全避免ADT。我们 假设（1）AGN及其吡喃香豆素在动物模型中的PCa拦截功效是 可扩展到人类PCa患者，给予足够的AGN剂量和暴露持续时间;（2）多个 包括免疫监视和炎症抑制的机制有助于临床癌症 拦截活动。科学前提是基于存在新型活性吡喃香豆素化合物 与大豆、茶、鱼油、乌藨子、蘑菇和大麻中的不同， 在动物癌症模型中的癌症疗效。此外，我们已经证明了a）口服生物利用度和有利的 啮齿动物和人类中的药代动力学（PK）指标; B）细胞色素P450（CYP 2C 19和3A 4首过 吡喃香豆素类化合物decursin（D）和decursinol angelate（DA）转化为它们的代谢物decursinol（DOH）; c）在小鼠靶前列腺中的去胡辛醇的熟练组织保留; 显示雄激素受体轴的独立性，避免ADT药物的副作用，使血PSA 癌症负荷的可靠读数; e）AGN增强免疫和减少炎症基因特征 在动物PCa模型中;和f）人类受试者中的单次AGN剂量增加自然杀伤[NK] mRNA 在他们的外周血单个核细胞中的特征和减少的IL-8趋化因子mRNA。我们建议3 RP后和RT后血浆PSA升高的患者的特定目标是“清洁”（由于前列腺已经 去除）并指示生物化学复发性PCa负荷。目标1.表征吡喃香豆素PK剂量 在12名患者中，对AGN补充和食物效应的反应成比例，以探测任何代谢上限， 尽量减少食物与草药的相互作用。目标2.评价两次PCa（PSA）拦截的安全性和复发疗效 在36名患者的I/II期试验中每日补充AGN。目标3.测量急性和重复给药PK指标， 与PSA相关的β 2C 19和3A 4代谢物状态以及免疫和炎症生物标志物的变化 结果。影响：安全性信息和有利的PSA缓解将指导未来的随机对照 用于预防或治疗前列腺癌和其他癌症的试验。关于PK剂量反应、重复给药PK的新知识 行为、遗传药理学和免疫生物标志物不仅填补了AGN补充剂的关键空白， 在癌症患者中，而且可用于肿瘤学以外的疾病预防和治疗。

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.