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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：
10652439
负责人：
PETER J HOUGHTON
金额：
$ 48.76万
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/10652439
关键词：
Acceleration Adolescent Adopted Alveolar Rhabdomyosarcoma Antibody-drug conjugates 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 Equity 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 Race Radiation therapy Relapse Renal carcinoma Reproducibility Research Resistance Resources Rhabdoid Cell 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 biomarker identification 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 radiation response radioresistant 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).

摘要