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)

• 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
• 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

 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（由申请人提供）：本申请是对RFA（C类：其他（非CNS）实体瘤体内试验研究计划）的回应，旨在筛选针对软组织肉瘤（尤文肉瘤、横纹肌肉瘤、其他ST肉瘤）和肾癌模型（肾母细胞瘤、横纹肌样瘤）的药物/组合。作为儿科临床前试验计划（PPTP）的一部分，该小组使用患者来源的异种移植物（PDX）和细胞系来源的异种移植物评价了80多种药物/组合。我们建立了12个横纹肌肉瘤（RMS）PDX模型（7个腺泡型[ARMS]，5个胚胎型[ERMS]），13个尤文肉瘤（EWS）模型（3个PDX）。此外，我们有2个腺泡状软组织肉瘤模型，透明细胞肉瘤和未分化肉瘤各一个。在肾脏肿瘤组中，我们开发了代表Wilms肿瘤（n=8，2例间变性）和5例非CNS恶性横纹肌样肿瘤的PDX模型。使用PPTP中开发的异种移植模型和SOP，该团队已证明能够提供高质量的可重现数据，评估已鉴定出已快速进入临床试验的实体的单一药物和组合。在早期儿科临床试验中被确定为具有生物学意义活性的特定药物和组合将成为研究部分假设驱动目标的焦点：假设1：新型抗有丝分裂药物艾日布林和abraxane将与肉瘤模型中的拓扑异构酶I毒物伊立替康具有协同相互作用。假设2. TOR激酶的抑制将下调DNA损伤修复蛋白FANCD 2，并使肉瘤对电离辐射治疗（XRT）敏感。假设3.由于肺泡软组织肉瘤（ASPS）表达非常高的膜相关糖蛋白GPNMB，这些肿瘤将对glembatumumab vedotin（一种靶向GPNMB的抗体-药物偶联物）敏感。此外，glembatumumab将与西地尼布和血管生成抑制剂协同作用，并且是这种罕见实体瘤的唯一确定的有效治疗剂。每项研究将纳入药效学指标，这些指标将告知协同作用的机制，或未能如预期那样协同作用。根据这些PD研究的结局和结果，将修改联合用药或联合用药顺序。总体目标是确定新的组合，可以为这些治疗儿童实体瘤的新药的临床开发提供信息。