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

基本信息

批准号：
10461141
负责人：
PETER J HOUGHTON
金额：
$ 58.77万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10461141
关键词：
Adolescent Adopted Alveolar Antibody-drug conjugates Biological Markers Biological Products 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 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

项目摘要

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).

抽象的儿童的癌症很少见，每年21岁的儿童诊断出约15,700例新病例或通过使用多模式疗法（手术，放射疗法和侵略性），美国年轻化学疗法），有70％的患者将被“治愈”，而5年无事件生存（EFS）超过 80％。因此，可以参加I/II期临床试验的患者人数很少，而且大多数患者将被广泛治疗，因此会耐药。因此，临床前研究准确地转化为有效的临床疗法是小儿药物开发的重要组成部分。我们的小组为通过儿童肿瘤学导致临床研究的PPTP/C研究做出了贡献组（COG）。重要的是，我们已经开发并表征了330多名患者衍生的异种移植物（PDX），从诊断和复发时从肿瘤中开发，可用于促进小儿药物的发展按照FDA在研究下的指示，以加速儿童的治疗和公平行为（儿童种族行为）。根据我们的研究，无论是在PPTC外部和外部，我们都建议使用肉瘤的PDX/CDX模型，肾癌和肝母细胞瘤来自高危患者，以鉴定新型药物和组合，并每年至少测试8-10个代理商，我们有专业知识。我们将探讨特定的假设将分子靶向剂与常规化学辐射处理，晚期药物递送整合系统（抗体 - 药物结合物，纳米颗粒），使用单鼠测试（SMT）作为主要筛选方法。在协作研究中，我们将评估一种新的人源化鼠标模型，其中测试免疫肿瘤剂是治疗这些PDX模型的优先事项。 PPTP/C的客观局限性之一测试是，可以在资源限制，这一数字显然不足以概括遗传/表观遗传异质性每种临床疾病。我们对PPTP数据的回顾性分析以及PPTC中最近的前瞻性测试，表明单个鼠标/肿瘤线与常规测试基本相似的数据（使用10只小鼠/组）对于每条肿瘤线）。 SMT设计的优点是，它允许多达20倍模型，更准确地表示每个小儿癌的遗传/表观遗传多样性资源约束。拟议的研究将采用SMT作为识别代理的主要筛选方法具有生物学意义的活性（即大抗肿瘤作用）并鉴定出异常的肿瘤响应者的验证。与PDX模型的分子表征相关的SMT方法，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，我们可以从本质上进行临床前II期试验，并更准确地模拟可能的临床反应率疾病。作为PED-IN Vivo-TP的一部分，我们旨在开发高风险的高效，毒性较小的疗法困扰儿童和青少年/年轻人（AYA）的癌症。