Development of Novel Herbal Therapy for Prevention of Irinotecan-induced Severe Delayed Onset Diarrhea

项目摘要/摘要 癌症是美国第二大死因。据美国癌症协会称 据统计，预计将有约176万新患者被诊断为癌症，约60万人 预计2019年美国将有人死于癌症。约占总数的6%-10% 癌症患者被诊断为IV期/转移性癌症，而30%-50%的患者在 疾病的发展。通过新的有效的癌症治疗药物的出现，5年存活率 癌症的发病率已提高到约67%，但难治性/复发性疾病的治疗在 转移性癌症患者仍然是一个严峻的挑战。在各种可供治疗的抗癌药物中 对于转移性癌症的治疗，伊立替康往往是治疗难治性疾病的最后手段。 最近的临床研究表明，大剂量伊立替康治疗可以成功地用于 患有难治性疾病的患者，即使是伊立替康难治的患者，也能延长预期寿命 癌症患者。然而，伊立替康目前的治疗是有限的，因为严重的，有时 危及生命的剂量限制部位效应(即中性粒细胞减少和严重延迟性腹泻)。 化疗引起的中性粒细胞减少症(低白细胞)可通过预防性治疗得到有效控制 抗生素和人粒细胞集落刺激因子制剂在临床上的应用但是，在 大约15%的患者接受伊立替康的标准护理治疗，目前腹泻是无法控制的 洛哌丁胺等药物，需要住院甚至停止治疗。此外，大多数 目前的治疗方法只能缓解症状，但不能防止对肠道日益严重的损害 伊立替康治疗的连续周期导致的功能和完整性。基于最近的 来自我们合作者实验室的初步数据，Sanarentero提议开发一种新的草药 能预防伊立替康腹泻毒性和肠道损伤的产品(SE_H1)。这 将有助于提高生活质量，降低治疗成本，通过减少 住院，并延长难治/复发转移性癌症患者的预期寿命 疾病，允许继续治疗和大剂量伊立替康治疗。具体的 此第一阶段SBIR提案的目的是：1)开发一种标准化的新型专利草药配方 使用Caco-2细胞；2)建立SDOD中成药配方的体内疗效 预防；以及3)标准化SE_H1的CMC(化学、制造和控制) 第二阶段研究。这个项目的成功将产生一个有特色的、标准化的、 安全有效的中成药产品预防伊立替康致重症 迟发性腹泻。它还将为我们提供有效性的概念验证证据和 临床前模型的安全性，因此降低了产品的风险，以便在第二阶段进行进一步开发 SBIR建议。

PROJECT SUMMARY / ABSTRACT Cancer is the second leading cause of death in the United States. According to American Cancer Society statistics, about 1.76 million new patients are expected to be diagnosed with cancer and about 600,000 people are expected to die due to cancer in the United States in 2019. Approximately 6-10% of the total cancer patients are diagnosed with stage IV/metastatic cancer, while 30-50% develop metastasis during disease progression. Through the advent of new and effective drugs for cancer treatment, 5-year survival rate for cancer has improved to about 67%, however treatment of refractory/recurrent disease in metastatic cancer patients remains a critical challenge. Among the various cancer drugs available for metastatic cancer treatment, irinotecan is often the drug of last resort for the refractory diseases. Recent clinical studies have indicated that high-dose irinotecan therapy can be successfully used in patients with refractory diseases, even in irinotecan-refractory patients, improving life expectancy of cancer patients. However, irinotecan treatment is currently limiting due to severe and sometimes life-threatening dose-limiting site effects (i.e. neutropenia and severe delayed onset diarrhea). Chemotherapy-induced neutropenia (low white blood cells) is effectively managed with prophylactic antibiotics and human G-CSF (granulocyte colony stimulating factor) agents in clinics. However, in about 15% of patients on standard of care irinotecan therapy, diarrhea is unmanageable with current drugs such as loperamide, requiring hospitalization and even cessation of therapy. Moreover, most current treatments only provide symptomatic relief but do not prevent the increasing damage to gut function and integrity, resulting with consecutive cycles of irinotecan therapy. Based on recent preliminary data from our collaborator’s lab, Sanarentero is proposing to develop a new herbal product (SE_H1) which can prevent the irinotecan-induced diarrheal toxicity and gut damage. This will help improve the quality of life, reduce the cost of treatment by reducing incidences of hospitalization, and increase the life expectancy of metastatic cancer patients with refractory/recurrent diseases, by allowing continuation of treatment and high-dose irinotecan therapy. The specific aims of this Phase I SBIR proposal are to 1) develop a standardized novel proprietary herbal formula using Caco-2 cells; 2) establish the in vivo efficacy of the proprietary herbal formula for SDOD prevention; and 3) standardize CMC (Chemistry, Manufacturing, and Controls) of SE_H1 for Phase II studies. Success of this project will generate a well-characterized, standardized, safe and efficacious proprietary herbal product for prevention of irinotecan-induced severe delayed onset diarrhea. It will also provide us with proof-of concept evidence of efficacy and safety in a preclinical model, therefore derisking the product for further development in phase II SBIR proposal.