Testicular effects of modern chemotherapy regimens in osteosarcoma survivors

现代化疗方案对骨肉瘤幸存者睾丸的影响

• 批准号: 10263892
• 负责人: MARGARETT SHNORHAVORIAN
• 金额: $ 80.39万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263892
• 关键词: Address; Adolescent and Young Adult; Adverse effects; Affect; Andrology; Antineoplastic Agents; Antineoplastic Protocols; Attention; Biological Assay; Biological Markers; Biometry; Blood; Blood specimen; Cancer Patient; Cancer Survivor; Chemotherapy-Oncologic Procedure; Childhood; Childhood Cancer Treatment; Cisplatin; Cyclophosphamide; DNA; DNA Methylation; Drug Storage; Epidemiology; Ewings sarcoma; Exposure to; Fertility; Future; Genetic Variation; Genomic DNA; Germ cell tumor; Gonadal Steroid Hormones; Gonadotropins; Health; High Prevalence; High-Throughput Nucleotide Sequencing; Ifosfamide; Immunoprecipitation; Infertility; Knowledge; Male Adolescents; Malignant Neoplasms; Measures; Metabolism; Methylation; Modernization; Morphology; Multicenter Studies; Oncology; Patient Self-Report; Patients; Population; Prevention strategy; Protocols documentation; Questionnaires; Randomized; Recording of previous events; Regimen; Research; Saliva; Sampling; Seminal fluid; Serum; Sperm Count Procedure; Spermatogenesis; Sterility; Steroid biosynthesis; Survivors; Testosterone; Therapeutic Trials; Toxic effect; Treatment Side Effects; Urology; Vertebral column; base; chemotherapy; childhood cancer survivor; drug action; epigenomics; fertility preservation; genome-wide; high risk; high risk population; inhibin B; male; methylation pattern; multidisciplinary; next generation sequencing; offspring; osteosarcoma; public health relevance; recruit; reproductive function; reproductive toxicity; sperm cell; sperm morphology; young adult

 DESCRIPTION (provided by applicant): Among the most important challenges faced by male childhood and adolescent and young adult (AYA) cancer survivors is the reproductive toxicity of cancer chemotherapy. Cisplatin and Ifosfamide form the backbone of chemotherapy for some of the most common childhood and young adult cancers, but there is a gap in knowledge regarding the effects of cisplatin, and the effects of ifosfamide without cyclophosphamide, on spermatogenesis and steroidogenesis in male AYA survivors of childhood cancer and non-germ cell cancer populations. DNA methylation changes are a possible mechanism of action of these drugs on testicular function. A better understanding of these effects will allow for identificationof high risk patients and better prevention strategies for testicular toxicity to be developed for pediatric and AYA cancer treatment protocols. This study will comprehensively evaluate the effects of cisplatin with or without ifosfamide on spermatogenesis and steroidogenesis among childhood and AYA survivors treated with modern chemotherapies for osteosarcoma. Specifically, our aims are: 1) Determine whether infertility and/or biomarkers of spermatogenesis and steroidogenesis differ in male osteosarcoma survivors treated with cisplatin with or without ifosfamide compared to male controls without a history of cancer; 2) Evaluate whether cisplatin with or without ifosfamide for the treatment of osteosarcoma is associated with sperm DNA methylation patterns. Osteosarcoma survivors will be recruited from two COG therapeutic trials [COG AOST0331 and INT0133 (CCG7921 and POG9351)], and controls identified and recruited through address-based sampling. Subjects will complete questionnaires and provide blood, saliva, and semen samples through a mail protocol. Blood samples will be analyzed for testosterone, FSH, LH, Inhibin B; genomic DNA extracted from saliva and stored for future studies of host genetic variation in metabolism of chemotherapeutic drugs storage; and sperm DNA will be assayed using genome-wide methylated DNA immunoprecipitation followed by next generation sequencing. The assembled team and consortium brings together multi-disciplinary expertise in urology, andrology, oncology, epidemiology, biostatistics, and epigenomics. Completion of the proposed research will be a major step towards informing male childhood and AYA cancer patients receiving similar regimens about the adverse effects of their treatment and towards identifying high risk groups that would benefit from targeted strategies for fertility preservation.

 描述（由适用提供）：在男性童年，青少年和年轻人（AYA）癌症存活中面临的最重要的挑战之一是癌症化学疗法的生殖毒性。对于一些最常见的童年和成年癌症，顺铂和ifosfamide构成了化学疗法的骨干，但是关于顺铂的影响以及无环磷酰胺，无环磷酰胺，精子发生和类固醇生成对雄性Ayya aya aya aya aya aya aya ayy ayy ayy ayy nayhohood coldhood cance癌症和非男性癌症癌症和非男性癌癌的影响。 DNA甲基化的变化是这些药物对测试功能的可能作用机理。对这些影响的更好理解将允许鉴定高风险患者，并为儿科和AYA癌症治疗方案开发出更好的预防策略。这项研究将全面评估顺铂具有或不具有ifosfamide的影响，对童年时期和用现代化学疗法治疗的骨肉瘤治疗的幼稚和AYA表面上的类固醇生成。具体而言，我们的目的是：1）确定与有或没有癌症史相比，用顺铂治疗的雄性骨肉素表面上的生生成和/或生物学的雄性骨肉瘤表面是否有不同； 2）评估有或没有ifosfamide治疗骨肉瘤的顺铂是否与精子DNA甲基化模式有关。骨肉瘤存活率将从两个COG治疗试验中招募 [COG AOST0331和INT0133（CCG7921和POG9351）]，并通过基于地址的采样来识别和招募对照。受试者将通过邮件协议填写问卷，并提供血液，唾液和精液样本。将分析血样的睾丸激素，FSH，LH，抑制素B；从唾液中提取的基因组DNA，并存储在化学治疗药物储存的代谢中宿主遗传变异的未来研究；将使用全基因组甲基化的DNA免疫沉淀进行分配的精子DNA，然后进行下一代测序。组装的团队和财团汇集了泌尿外科，雄科学，肿瘤学，流行病学，生物统计学和表观基因组学方面的多学科专业知识。拟议研究的完成将是告知男性童年时期和AYA癌症患者的重大步骤，这些患者接受了类似的治疗方案，并朝着确定将受益于生育能力的有针对性策略受益的高风险群体。