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

项目总结/摘要 癌症是美国第二大死亡原因。根据美国癌症协会 据统计，预计将有约176万新患者被诊断患有癌症， 预计2019年美国将有1000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%的癌症患者在治疗期间发生转移。 疾病进展。通过新的有效的癌症治疗药物的出现，5年生存率 癌症的发病率已提高到约67%，然而， 转移性癌症患者仍然是一个关键的挑战。在各种癌症药物中， 转移性癌症的治疗，伊立替康往往是难治性疾病的最后药物。 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 难治性疾病患者，即使是伊立替康难治性患者，预期寿命延长 的癌症患者。然而，伊立替康治疗目前是有限的，由于严重的，有时是有限的。 危及生命的剂量限制性部位效应（即中性粒细胞减少症和重度迟发性腹泻）。 化疗诱导的中性粒细胞减少症（低白色血细胞）可通过预防性治疗有效管理 抗生素和人G-CSF（粒细胞集落刺激因子）制剂。但在 在接受伊立替康标准治疗的患者中，约15%的腹泻是目前无法控制的。 药物如洛哌丁胺，需要住院治疗，甚至停止治疗。而且大部分 目前的治疗方法只能缓解症状， 功能和完整性，导致伊立替康治疗的连续周期。根据最近 根据我们合作者实验室的初步数据，Sanarengland正计划开发一种新的草药， 产品（SE_H1），可预防伊立替康诱导的结肠毒性和肠道损伤。这 将有助于提高生活质量，通过减少 住院治疗，并延长难治性/复发性转移性癌症患者的预期寿命 疾病，允许继续治疗和高剂量伊立替康治疗。具体 第一阶段SBIR提案的目标是：1）开发标准化的新型专利草药配方 使用Caco-2细胞; 2）建立用于SDOD的专有草药配方的体内功效 预防;和3）标准化SE_H1的CMC（化学、生产和控制）， II期研究。该项目的成功将产生一个特点鲜明，标准化， 用于预防伊立替康引起的严重 迟发性腹泻它还将为我们提供有效性的概念验证证据， 临床前模型中的安全性，因此降低了产品在II期进一步开发的风险 SBIR提案。

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.