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

 描述(由申请人提供)：本申请是为了响应RFA(C型：其他(非中枢神经系统)实体肿瘤体内测试的研究计划)，以筛选抗软组织肉瘤(尤文肉瘤、横纹肌肉瘤、其他ST肉瘤)和肾癌模型(Wilms瘤、横纹肌肉瘤)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对80多种药物/组合进行了评估。我们建立了12个横纹肌肉瘤(RMS)PDX模型(7个肺泡型[ARM]，5个胚胎型[ERMS])，13个尤文肉瘤(EWS)模型(3个PDX)。此外，我们还建立了2个肺泡软组织肉瘤模型，透明细胞肉瘤和未分化肉瘤各1个。在肾肿瘤小组，我们建立了代表肾母细胞瘤(8例，2例间变性)和5例非中枢神经系统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，该团队展示了提供高质量、可重复性的数据的能力，这些数据评估了已识别出已迅速进入临床测试的实体的单一药物和组合。特定的药物和组合，被确定为具有生物学意义的活性，以及在早期的儿科临床试验中，将是假说驱动的研究组成部分目标的重点：假设1：新型抗有丝分裂药Eribuin和Abraxane将与拓扑异构酶I毒药伊立替康在肉瘤模型中具有协同作用。假设2.抑制TOR激酶将下调DNA损伤修复蛋白FANCD2，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，这些肿瘤将对针对GPNMB的抗体-药物结合物glembatumab vedotin敏感。此外，格伦巴图单抗将与头孢拉尼和血管生成抑制剂协同作用，是唯一已确定的治疗这种罕见实体肿瘤的有效方法。每项研究都将纳入药效学措施，以了解协同作用的机制，或未能如预期那样发挥协同作用。根据结果和这些PD研究的结果，组合或组合的顺序将被修改。总体目标是确定能够为这些治疗儿童实体肿瘤的新药物的临床开发提供信息的新组合。

 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.