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

确定用于治疗儿科和 AYA 高风险肉瘤、肾癌和肝癌的新药的测试计划

• 批准号: 10300383
• 负责人: PETER J HOUGHTON
• 金额: $ 60.07万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10300383
• 关键词: Adolescent; Adopted; Alveolar; Antibody-drug conjugates; Biological; Biological Markers; Brain Neoplasms; CD276 gene; Cell Line; Characteristics; Child; Childhood; Childhood Cancer Treatment; Childhood Solid Neoplasm; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Cyclophosphamide; DNA Damage; DNA Repair; Data; Databases; Development; Diagnosis; Disease; Disease-Free Survival; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Targeting; Embryonal Rhabdomyosarcoma; Enrollment; Epigenetic Process; Ewings sarcoma; Experimental Designs; Foundations; Genetic; Goals; Growth; Hepatoblastoma; Heterogeneity; High-Risk Cancer; Immunooncology; In complete remission; Investigation; Life; Link; Lipids; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEKs; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Molecular; Molecular Target; Mus; Mutation; Nephroblastoma; New Agents; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pediatric Oncology Group; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Pre-Clinical Model; Preclinical Testing; Probability; Protocols documentation; ROR1 gene; Radiation therapy; Relapse; Renal carcinoma; Reproducibility; Research; Resistance; Resources; Rhabdoid Tumor; Rhabdomyosarcoma; Signal Transduction; Sirolimus; Solid Neoplasm; Surface; Test Result; Testing; Therapeutic; Translating; Trastuzumab; United States National Institutes of Health; Validation; Vinca Alkaloids; Xenograft Model; Xenograft procedure; antitumor effect; base; cancer cell; cancer type; chemoradiation; chemotherapy; clinical development; design; disorder risk; efficacy evaluation; exceptional responders; exome sequencing; expectation; high risk; high risk population; humanized mouse; improved; in vivo; inhibitor/antagonist; irinotecan; kidney clear cell sarcoma; leukemia; mouse model; mutant; nano; nanoformulation; nanoparticle; nanosystems; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; patient stratification; pediatric drug development; pediatric patients; phase II trial; pre-clinical; preclinical study; programs; prospective test; public-private partnership; radiation resistance; radioresistant; repaired; response; response biomarker; sarcoma; screening; small molecule; success; systemic toxicity; targeted agent; transcriptome sequencing; translational impact; tumor; young adult

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).

抽象的 儿童癌症很少见，每年大约有 15,700 例 21 岁或 21 岁儿童新诊断病例 在美国，通过使用多学科治疗（手术、放射治疗和积极的治疗），年轻化 化疗），70% 的患者的疾病将被“治愈”，并且 5 年无事件生存期 (EFS) 超过 80%。因此，能够参加I/II期临床试验的患者数量很少，而且大多数 患者将接受广泛治疗，因此具有药物/放射抵抗力。因此，临床前研究表明 准确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，我们已经开发并表征了超过 330 个患者来源的异种移植物 (PDX)， 在诊断和复发时由肿瘤发展而来，可用于促进儿科药物开发 按照 FDA 根据《加速治疗和儿童公平研究法案》（RACE for Children 行为）。根据我们在 PPTC 内外的研究，我们建议使用肉瘤的 PDX/CDX 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， 每年测试至少 8-10 个代理，我们对此有专业知识。我们将探讨具体的假设 将分子靶向药物与传统放化疗、先进药物输送相结合 系统（抗体药物偶联物、纳米颗粒），以及使用单鼠测试（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 免疫肿瘤药物是治疗这些 PDX 模型的首要任务。 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遗传/表观遗传异质性 各临床疾病。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， 表明单个小鼠/肿瘤系提供的数据与传统测试基本相似”（使用 10 只小鼠/组） 对于每个肿瘤系）。 SMT 设计的优势在于它允许并入多达 20 倍的器件 模型，更准确地代表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。拟议的研究将采用 SMT 作为识别药物的主要筛选方法 具有生物学意义的活性（即大的抗肿瘤作用）并识别“特殊”的肿瘤 响应者进行验证。当 SMT 方法与 PDX 模型的分子表征联系起来时， 可能会增加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 期试验并更准确地模拟给定情况下可能的临床反应率 疾病。作为 Ped-In Vivo-TP 的一部分，我们的目标是为高危患者开发高效、毒性较小的疗法 困扰儿童和青少年/年轻人的癌症 (AYA)。