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：
9315791
负责人：
PETER J HOUGHTON
金额：
$ 61.04万
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/9315791
关键词：
Abraxane Adult Alveolar Alveolar Rhabdomyosarcoma Alveolar Soft Part Sarcoma Angiogenesis Inhibitors Antibody-drug conjugates Antimitotic Agents Biological Biological Products Cancer Model Carcinoma Cell Line Cell surface Childhood Childhood Cancer Treatment Childhood Solid Neoplasm Chromosomal translocation Clear Cell Sarcoma Clinical Clinical Trials Cytotoxic Chemotherapy Cytotoxic agent DNA Repair Data Disease Disease-Free Survival Dose EWSR1 gene Ewings sarcoma FANCD2 protein FLI1 gene FOXO1A gene Failure Genetic Glycoproteins Ionizing radiation Kidney Neoplasms Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Measures Membrane Modality Modeling Molecular Target 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 Reproducibility Research Rhabdoid Tumor Rhabdomyosarcoma Signal Pathway Signal Transduction Signal Transduction Inhibitor Soft tissue sarcoma Solid Neoplasm TP53 gene Testing Therapeutic Topoisomerase Treatment Efficacy Undifferentiated Vincristine Xenograft Model Xenograft procedure actionable mutation base cancer cell childhood cancer mortality childhood sarcoma clinical development cytotoxic in vivo inhibitor/antagonist irinotecan kinase inhibitor mortality novel novel therapeutics osteosarcoma prevent programs public health relevance research clinical testing response sarcoma screening standard of care synergism targeted agent tumor

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.

描述（应用程序提供）：此应用是响应RFA（C型：在体内的其他（非CNS）实体瘤测试的研究计划），以筛选针对软组织肉瘤的剂/组合（Ewing Sarcoma，Rhabdomomyosarcoma，其他St Sarcomas，其他St Sarcomas）和肾脏癌症模型（Wilms tumor，Rhabdoid）。作为小儿临床前测试计划（PPTP）的一部分，该组使用患者衍生的异种移植物（PDX）和细胞系衍生的异种移植物评估了80多种代理/组合。我们已经开发了12种横纹肌肉瘤（RMS）PDX模型（7个肺泡[臂]，5个胚胎[ERMS]），13个Ewing肉瘤（EWS）模型（EWS）模型（3 pdx）。此外，我们有2个肺泡软零件肉瘤模型，各种肉瘤和未分化的肉瘤中各个。在肾脏肿瘤面板中，我们开发了代表Wilms肿瘤的PDX模型（n = 8，2播种机）和5个非CNS恶性肿瘤性横纹肌肿瘤。使用PPTP中开发的异种移植模型和SOP，该团队证明了能够提供高质量，可重现的数据，以评估已确定已迅速转化为临床测试的实体的单个代理和组合。特定的药物和组合被确定为具有生物学上有意义的活性，在早期的小儿临床试验中，研究成分的假设驱动目标的重点将是：假设1：这种新型的抗魔法药物，Eribulin和abraxane将具有与拓扑酶I Peotio，Irinotecan模型的协同相互作用。假设2。对TOR激酶的抑制作用将下调DNA损伤修复蛋白fancd2和对电离放射治疗（XRT）的敏感肉瘤。假设3。由于肺泡软部分肉瘤（ASP）表达了非常高的膜相关糖蛋白GPNMB，因此这些TUMS将对靶向GPNMB的抗体 - 毒剂 - 固定蛋白（一种抗体 - 药物 - 毒剂）敏感。此外，Glembatumumumumab将与Cediranib和血管生成抑制剂合成，并且是该稀有实体瘤的唯一有效疗法。每项研究都将纳入药物学指标，以告知协同机理或未能按预期合成。根据这些PD研究的结果和结果，将修改组合的组合或测序。总体目的是确定可以为这些新药物治疗儿童实体瘤的临床发展提供新的组合。