A Testing Program to Identify Novel Agents for Treatment of Pediatric and AYA High-Risk Sarcoma, Kidney and Liver Cancer

摘要 儿童癌症是罕见的，每年约有15，700例新病例诊断为21岁或以上的儿童。 通过使用多模式治疗（手术，放射治疗和积极治疗）， 化疗），70%的患者将“治愈”他们的疾病，5年无事件生存期（EFS）超过 百分之八十因此，可入组I/II期临床试验的患者数量很少，大多数患者都是在临床试验中接受治疗的。 患者将接受广泛治疗，因此具有药物/放射抗性。因此，临床前研究 准确地转化为有效的临床治疗是儿科药物开发的重要组成部分。我们 该小组为PPTP/C的研究做出了贡献，这些研究导致了儿童肿瘤学的临床研究 组（COG）。重要的是，我们已经开发和表征了超过330种患者来源的异种移植物（PDX）， 从诊断和复发时的肿瘤发展而来，可用于促进儿科药物开发 根据FDA在《加速儿童治愈和公平研究法案》（RACE for Children）下的指导， Act）。基于我们在PPTC内外的研究，我们建议使用肉瘤的PDX/CDX模型， 肾癌和来自高危患者的肝母细胞瘤，以鉴定新的药剂和组合， 每年至少测试8-10个代理商，这是我们的专长。我们将探讨具体的假设， 将分子靶向药物与常规化学-放射治疗、先进药物递送 系统（抗体-药物偶联物，纳米颗粒），并使用单小鼠测试（SMT）作为主要的 筛选方法。在合作研究中，我们将评估一种新的人源化小鼠模型， 免疫肿瘤学试剂是治疗这些PDX模型的优先选择。PPTP/C的客观局限性之一 测试的结果是，相对较少的肿瘤模型，代表一个特定的疾病（n=3-8/疾病），可用于 资源限制，一个数字显然不足以概括的遗传/表观遗传异质性， 每一种临床疾病我们对PPTP数据的回顾性分析，以及最近在PPTC中的前瞻性测试， 显示单个小鼠/肿瘤系给出与常规测试（使用10只小鼠/组）基本相似的数据 对于每个肿瘤线）。SMT设计的优点是，它允许将多达20倍的 模型，更准确地代表了同一区域内每种儿科癌症的遗传/表观遗传多样性， 资源限制。建议的研究将采用SMT作为识别病原体的主要筛查方法 具有生物学意义的活性（即大的抗肿瘤作用）并鉴定出“异常”的肿瘤 响应者进行验证。SMT方法，当与PDX模型的分子表征相关联时， 潜在地增加了识别与应答相关的生物标志物的能力。使用SMT，我们基本上可以 进行临床前II期试验，并更准确地模拟给定条件下可能的临床反应率。 疾病作为Ped-In Vivo-TP的一部分，我们的目标是为高风险患者开发高效，毒性较小的治疗方法。 儿童和青少年/年轻人（AYA）的癌症。

ABSTRACT Cancer in children is rare with approximately 15,700 new cases diagnosed annually in children 21 years or younger in the U.S. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be `cured' of their disease, and 5-year Event-Free Survival (EFS) exceeds 80%. Consequently, the number of patients that can be enrolled in phase I/II clinical trials is small, and most patients will have been extensively treated, hence drug/radiation resistant. Thus, preclinical studies that accurately translate into effective clinical therapy are an essential component of pediatric drug development. Our group has contributed to studies in the PPTP/C that have led to clinical studies through Children's Oncology Group (COG). Of importance, we have developed and characterized over 330 Patient Derived Xenografts (PDX), developed from tumors both at diagnosis and relapse, that can be used to facilitate pediatric drug development as directed by FDA under the Research to Accelerate Cures and Equity for Children Act (RACE for Children Act). Based on our studies, both in and outside the PPTC, we propose to use PDX/CDX models of sarcoma, kidney cancer, and hepatoblastoma derived from high-risk patients to identify novel agents and combinations, and to test at least 8-10 agents per year, for which we have expertise. We will explore specific hypotheses to integrate molecular-targeted agents with conventional chemo-radiation treatment, advanced drug delivery systems (antibody-drug conjugates, nanoparticles), and the use of Single Mouse Testing (SMT) as the primary screening approach. In collaborative studies, we will evaluate a new humanized mouse model where testing of immuno-oncology agents is a priority to treat these PDX models. One of the objective limitations of PPTP/C testing was that relatively few tumor models representing a specific disease (n=3-8/disease) could be used within the resource constraints, a number clearly insufficient to recapitulate the genetic/epigenetic heterogeneity of each clinical disease. Our retrospective analysis of PPTP data, and recent prospective testing in the PPTC, shows that a single mouse/tumor line gives essentially similar data to conventional testing' (using 10 mice/group for each tumor line). The advantage of the SMT design is that it allows for incorporation of up to 20-fold more models, more accurately representing the genetic/epigenetic diversity of each pediatric cancer within the same resource constraints. The proposed studies will adopt SMT as the primary screening approach to identify agents that have biologically meaningful activity (i.e. large antitumor effects) and identify tumors that are `exceptional responders' for validation. The SMT approach, when linked to the molecular characterization of PDX models, potentially increases the power to identify biomarkers associated with response. Using SMT we can essentially conduct preclinical phase II trials and simulate the likely clinical response rate more accurately for a given disease. As part of the Ped-In Vivo-TP, we aim to develop highly effective, less toxic therapies for high-risk cancers that afflict children and adolescents/young adults (AYA).