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

摘要 儿童癌症很少见，21岁或以上儿童每年约有15,700例新确诊病例。 通过使用多模式治疗(手术、放射治疗和攻击性治疗)在美国变得年轻 化疗)，70%的患者将被治愈，5年无事件生存(EFS)超过 80%。因此，可以登记参加I/II期临床试验的患者数量很少，而且大多数 患者将得到广泛的治疗，因此对药物/辐射具有抗药性。因此，临床前研究表明 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。我们的 小组对PPTP/C的研究做出了贡献，这些研究通过儿童肿瘤学导致了临床研究 组(COG)。重要的是，我们已经开发并鉴定了330多例患者来源的异种移植物(PDX)， 从确诊和复发的肿瘤发展而来，可用于促进儿科药物的开发 按照FDA根据《加快儿童治疗和公平研究法案》(RACE For Children)的指示 行动)。基于我们在PPTC内外的研究，我们建议使用PDX/CDX肉瘤模型， 来自高危患者的肾癌和肝母细胞瘤，以确定新的药物和组合， 每年至少测试8-10个代理，我们有这方面的专业知识。我们将探索具体的假设，以 将分子靶向药物与传统的放化疗、先进的药物输送 系统(抗体-药物结合物、纳米颗粒)和使用单鼠试验(SMT)作为主要方法 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，其中测试 免疫肿瘤学药物是治疗这些PDX模型的首选药物。PPTP/C的客观局限性之一 测试表明，代表特定疾病(n=3-8/疾病)的肿瘤模型相对较少。 资源限制，这个数字显然不足以概括基因/表观遗传的异质性 每种临床疾病。我们对PPTP数据的回顾分析，以及最近在PPTC进行的前瞻性测试， 显示单个小鼠/肿瘤系给出的数据基本上与传统测试相似(使用10只小鼠/组 对于每个肿瘤系)。SMT设计的优点是它允许合并多达20倍的 模型，更准确地表示同一内每个儿科癌症的遗传/表观遗传多样性 资源限制。拟议的研究将采用SMT作为主要筛选方法来识别制剂。 具有生物学意义的活性(即巨大的抗肿瘤作用)，并识别出异常的肿瘤 用于确认的响应者。SMT方法，当与PDX模型的分子表征相联系时， 潜在地增加了识别与反应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，更准确地模拟给定条件下可能的临床应答率 疾病。作为Ped-in Vivo-TP的一部分，我们的目标是为高危患者开发高效、毒性较低的疗法 折磨儿童和青少年/年轻人的癌症(Aya)。

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).