Development of mechanism-based ovarian reserve protecting adjuvant therapies against gonadotoxic therapeutic agents

开发基于机制的卵巢储备保护辅助疗法以对抗性腺毒性治疗剂

• 批准号: 9817008
• 负责人: So-Youn Kim
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817008
• 关键词: Adjuvant; Adjuvant Therapy; Apoptosis; Apoptotic; Cancer Patient; Cardiovascular Diseases; Categories; Cessation of life; Clinical; DNA Damage; Data; Development; Disease; Embryo; Endocrine; FOXO3A gene; Female; Fertility; Functional disorder; Future; Germ Cells; Goals; Growing Follicle; Guidelines; Health; Hormone Responsive; Iatrogenesis; Infertility; Intervention; Knockout Mice; Life; Malignant Childhood Neoplasm; Medical; Mus; Oocytes; Osteoporosis; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Patients; Preclinical Testing; Primordial Follicle; Proto-Oncogene Protein c-kit; Puberty; Safety; Savings; Signal Pathway; Survival Rate; Technology; Testing; Therapeutic Agents; Toxic effect; Treatment Efficacy; Woman; base; burnout; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; cost; effective intervention; egg; girls; improved; inhibitor/antagonist; leukemia; mouse model; mullerian-inhibiting hormone; novel; ovarian reserve; prepuberty; primary ovarian insufficiency; side effect; survival outcome; theories; young cancer survivor

PROJECT SUMMARY/ABSTRACT The five-year survival rate of cancer patients has improved in the last thirty years. The survival rate of pediatric cancers has reached 80%, and the young cancer survivors go on to live generally normal lives due to their life- saving treatments. Although advances in cancer therapies increased the survival rate, these therapies have long-term adverse health effects. One of the most serious side effects of those therapies is the off-target effect on germ cells. It causes the loss of primordial follicles that consist of ovarian reserve, which is defined as all of the follicles in the ovary available for future fertility and endocrine support for women. This treatment results in premature ovarian insufficiency, which clinically presents as endocrine dysfunction and infertility. Prepubertal kids who are treated with cancer therapies cannot initiate puberty and need medical help for maintaining their normal life. Thus, developing an effective intervention is an unmet need in the field. It has been proposed that certain intervention agents have the efficacy to protect ovarian reserves from cancer therapies. However, the mechanisms underlying the fertoprotective effects of these adjuvant therapies remain largely speculative. Therefore, our goals are to clarify the mechanisms on how gonadotoxic therapies deplete primordial follicles in the ovarian reserve, develop novel fertoprotective agents based on the mechanisms of primordial follicle depletion, and mechanistically match adjuvant fertoprotective strategies with specific gonadotoxic treatments. Several theories have been proposed to explain the mechanism of primordial follicle loss. The "burn out" theory is that chemotherapeutic agents activate dormant primordial follicles through an activation pathway. Another theory is that chemotherapeutic agents destroy primordial follicles through an “apoptotic pathway” due to high sensitivity to DNA damage. Our preliminary data suggest that there are two distinct apoptotic pathways in oocyte death in primordial follicles by DNA damages. Guided by strongly supported preliminary data, we propose to test 6 common chemotherapeutic agents and signaling pathway-based inhibitors (1) to elucidate the mechanisms of ovarian reserve depletion by 6 common gonadotoxic agents, (2) to elucidate the cellular mechanism of primordial follicle depletion by gonadotoxic agents in genetically modified mouse models, and (3) to examine the efficacy and safety of ovarian reserve-protecting adjuvant therapies. Our proposed studies will have a significant impact on the field by (1) clarifying mechanisms by which specific chemotherapeutic agents deplete primordial follicles, and by (2) testing the preclinical fertoprotective efficacy and safety of candidate adjuvants against specific chemotherapeutic agents. Our studies may inform guidelines for strategic selection of fertoprotective agents based on the mechanism of action against common gonadotoxic agents to prepubertal kids who will be treated with cancer therapies.

项目概要/摘要 过去三十年来，癌症患者的五年生存率有所提高。 癌症发病率已达到80%，年轻的癌症幸存者继续过着正常的生活，因为他们的生活—— 尽管癌症治疗的进步提高了生存率，但这些疗法已经 这些疗法最严重的副作用之一是脱靶效应。 它会导致由卵巢储备组成的原始卵泡的丧失，卵巢储备被定义为所有的卵巢储备。 卵巢中的卵泡可用于女性未来的生育和内分泌支持。 卵巢早衰，临床表现为内分泌功能障碍和不孕。 接受癌症治疗的孩子无法进入青春期，需要医疗帮助来维持青春期 因此，有人提出，制定有效的干预措施是该领域尚未满足的需求。 某些干预药物能够有效保护卵巢储备免受癌症治疗的影响。 这些辅助疗法的生育保护作用的机制在很大程度上仍然是推测性的。 因此，我们的目标是阐明性腺毒性疗法如何消耗原始卵泡的机制 卵巢储备功能，基于原始卵泡机制开发新型生育保护剂 耗尽，并将辅助生育保护策略与特定的性腺毒性治疗机械地匹配。 已经提出了几种理论来解释原始卵泡损失的机制，即“倦怠”理论。 化疗药物通过另一种激活途径激活休眠的原始卵泡。 理论认为，化疗药物通过“细胞凋亡途径”破坏原始卵泡，这是由于高浓度 我们的初步数据表明卵母细胞中有两种不同的细胞凋亡途径。 在强有力的初步数据的指导下，我们建议进行测试。 6种常见化疗药物和信号通路抑制剂（1）阐明其机制 6 种常见性腺毒性药物导致卵巢储备耗竭，(2) 阐明原始性的细胞机制 在转基因小鼠模型中用性腺毒性药物消除卵泡，以及（3）检查功效 我们提出的研究将产生重大影响。 通过（1）阐明特定化疗药物消耗原始卵泡的机制， (2) 测试候选佐剂针对特定药物的临床前生育保护功效和安全性 我们的研究可为生育保护剂的战略选择指南提供信息。 基于针对将要接受治疗的青春期前儿童的常见性腺毒性药物的作用机制 与癌症疗法。