(PQ9) Characterization and prophylactic treatment of chemotherapy-induced long-term adverse sequelae

癌症化疗会引起急性不良反应(如中性粒细胞减少、恶心、脱发) 可治疗的或暂时的。然而，临床证据表明，癌症化疗也会导致慢性 许多健康器官和组织(造血和免疫系统、中枢和外周神经)的损伤 系统、肺、胃肠、心血管和生殖系统)。这些不利影响限制了 可以给予的化疗药物的剂量，并降低其根除癌症的效果。慢性病患者 不良后遗症在治疗完成后很长一段时间内持续存在，并危及许多人的长期健康。 病人。然而，化疗对血管功能的不良长期影响的特征 健康组织器官与治疗相关疾病的病因及预防研究 才刚刚开始。 国际癌症研究机构报告称，新的癌症病例数量将从 到2025年，每年将达到1400万到1900万。由于癌症患者的长期存活率持续提高， 化疗带来长期不良后果的癌症幸存者人数正在稳步增加。 根据美国癌症协会的数据，美国目前有超过1370万癌症幸存者，预计这一数字将 到2022年增长到1800万。癌症患者存活频率的稳步增加是必要的 化疗对健康组织和器官的长期影响特征及寻找治疗方法 最小化它们。 这一跨学科和高度创新的项目将利用临床前乳腺癌荷瘤小鼠模型。 结合乳腺癌的化疗和细菌和病毒感染的小鼠模型来(1)定义 化疗对造血和免疫系统功能的长期影响及其临床意义 对新的和复发的感染的反应，(2)调查炎症在导致化疗中的作用- 在造血和免疫系统中诱发长期不良后遗症，并测试是否(3) 同时给予化疗和抗炎药物，以及新的靶向递送 化疗药物进入原发肿瘤是减少或预防肿瘤的有效新策略 化疗引起的长期不良后遗症。 这项研究的结果可以为(A)的翻译和临床测试提供一个重要的平台。 抗炎治疗作为癌症患者化疗的新辅助治疗；及(B) 新靶向原发肿瘤的化疗药物作为减少(1)的新方法 与治疗相关的长期后遗症，(2)提高治疗效果，(3)提高癌症治愈率，(4) 改善癌症患者的长期健康。

Cancer chemotherapy causes acute adverse effects (e.g. neutropenia, nausea, hair loss) which are treatable or are temporary. However, clinical evidence shows that cancer chemotherapy also causes chronic injury of many healthy organs and tissues (hematopoietic and immune systems, central and peripheral nervous system, pulmonary, gastrointestinal, cardiovascular and reproductive systems). These adverse effects limit the dose of chemotherapy drugs that can be given and diminish their efficacy to eradicate cancer. The chronic adverse aftereffects persist long after completion of therapy and jeopardize the long-term health of many patients. However, the characterization of adverse long-term effects of chemotherapy on the function of healthy tissues and organs, and the research on the causes and prevention of treatment related morbidities are just beginning. The International Agency for Cancer Research reported that the number of new cancer cases will rise from 14 to 19 million per year by 2025. Since the long-term survival rates of cancer patients continue to improve, the number of cancer survivors with long-term adverse consequences from chemotherapy is steadily increasing. According to ACS there are now over 13.7 million cancer survivors in the US, with that number expected to grow to 18 million by 2022. Steady increase in the frequency of patients surviving cancer necessitates characterization of long-term effects of chemotherapy on healthy tissues and organs and finding approaches to minimize them. This interdisciplinary and highly innovative project will utilize preclinical breast tumor-bearing mouse models combined with chemotherapy for breast cancer and mouse models of bacterial and viral infections to (1) define long-lasting effects of chemotherapy on the function of hematopoietic and immune systems and their responses to new and recurring infections, (2) investigate the role of inflammation in causing chemotherapy- induced long-term adverse sequelae in the hematopoietic and immune systems, and test whether (3) concurrent administration of chemotherapy and anti-inflammatory drugs, and novel targeted delivery of chemotherapy drugs into the primary tumors represent effective new strategies to decrease or prevent chemotherapy-induced long-term adverse sequelae. The outcomes of this research could provide a significant platform for translational and clinical testing of (a) anti-inflammatory treatment as new adjunct therapy for cancer patients undergoing chemotherapy, and (b) novel targeted delivery of chemotherapy drugs into the primary tumors as new approaches to (1) reduce treatment-related long-term sequelae, (2) improve treatment efficacy, (3) increase cancer cure rate, and (4) improve the long-term health of cancer patients.