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Pediatric Preclinical Testing Consortium: Research Programs Non-CNS (U01)

儿科临床前测试联盟：非 CNS 研究项目 (U01)

基本信息

批准号：
8968480
负责人：
PETER J HOUGHTON
金额：
$ 60.84万
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：
2015
资助国家：
美国
起止时间：
2015-07-07 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968480
关键词：
Abraxane Adult Alveolar Alveolar Rhabdomyosarcoma Alveolar Soft Part Sarcoma Angiogenesis Inhibitors Antibodies Antimitotic Agents Biological Products Cancer Model Carcinoma Cell Line Cell surface Child Childhood Childhood Cancer Treatment Childhood Solid Neoplasm Chromosomal translocation Clear Cell Sarcoma Clinical Clinical Trials Cytotoxic Chemotherapy Cytotoxic agent DNA Repair Data Development Disease Disease-Free Survival Dose EWSR1 gene Ewings sarcoma FANCD2 protein FLI1 gene Failure Genetic Glycoproteins Ionizing radiation Kidney Neoplasms Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Measures Membrane Modality Modeling Mutation Nephroblastoma New Agents Outcome PAX3 gene Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Poison Preclinical Testing Protocols documentation Radiation Radiation therapy Rare Diseases Relapse Renal carcinoma Reporting Research Rhabdoid Tumor Rhabdomyosarcoma Signal Pathway Signal Transduction Signal Transduction Inhibitor Solid Neoplasm TP53 gene Testing Therapeutic Type I DNA Topoisomerases Undifferentiated Vincristine Xenograft Model Xenograft procedure base cancer cell childhood sarcoma cytotoxic in vivo inhibitor/antagonist irinotecan kinase inhibitor mortality novel novel therapeutics osteosarcoma prevent programs public health relevance research clinical testing response sarcoma screening soft tissue standard of care tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): This application is in response to the RFA (Type C: Research Program for other (non-CNS) solid tumors testing in vivo) to screen agents/combinations against soft tissue sarcoma (Ewing sarcoma, rhabdomyosarcoma, other ST sarcomas) and kidney cancer models (Wilms tumor, rhabdoid). This group has evaluated over 80 agents/combinations using Patient Derived Xenografts (PDX) and cell line derived xenografts as part of the Pediatric Preclinical Testing Program (PPTP). We have developed 12 rhabdomyosarcoma (RMS) PDX models (7 alveolar [ARMS], 5 embryonal [ERMS]), 13 Ewing sarcoma (EWS) models (3 PDX). Additionally, we have 2 alveolar soft part sarcoma models and one each of clear cell sarcoma and undifferentiated sarcoma. In the kidney tumor panel we have developed PDX models representing Wilms tumors (n=8, 2 anaplastic), and 5 non-CNS malignant rhabdoid tumors. Using the xenograft models and SOPs developed in the PPTP, this team has demonstrated capability to provide high-quality, reproducible data evaluating single agents and combinations that have identified entities that have moved rapidly to clinical testing. Specific agents and combinations, identified as having biologically meaningful activity, and in early pediatric clinical trials will be the focus of the hypothesis-driven Aims of the research component: Hypothesis 1: That novel antimitotic agents, eribulin and abraxane will have synergistic interaction with the topoisomerase I poison, irinotecan in sarcoma models. Hypothesis 2. That inhibition of TOR kinase will downregulate the DNA damage repair protein FANCD2 and sensitize sarcomas to ionizing radiation therapy (XRT). Hypothesis 3. Because alveolar soft part sarcomas (ASPS) express very high membrane-associated glycoprotein GPNMB, these tumors will be sensitive to glembatumumab vedotin, an antibody-drug conjugate that targets GPNMB. Further, that glembatumumab will synergize with cediranib, and inhibitor of angiogenesis, and the only identified effective therapeutic for this rare solid tumor. Each study will incorporate pharmacodynamics measures that will inform as to the mechanism of synergy, or failure to synergize as anticipated. Based on outcomes, and results of these PD studies, combinations or sequencing of combinations will be modified. The overall objective is to identify novel combinations that can inform clinical development of these new agents for treatment of childhood solid tumors.