Pediatric Preclinical Testing Consortium

 描述（由申请人提供）：患有播散性神经母细胞瘤的儿童尽管接受了强化化疗、放疗和免疫治疗，但治疗失败和死亡的风险非常高。我们实验室的长期目标是通过开发针对每个病例独特致癌驱动因素的患者特异性疗法来大幅提高神经母细胞瘤的治愈率。在儿科临床前测试联盟（PPTC）的背景下，我们提出了一个神经母细胞瘤研究计划，该计划建立在丰富注释和高度表征的患者来源的异种移植物（PDX）和其他小鼠模型上。本项目中要检验的中心假设是，可以通过基于经验证和临床可测量的生物标志物的合理设计的组合疗法来定义和利用神经母细胞瘤的致癌驱动因素。通过我们专注于神经母细胞瘤和我们在前儿科临床前测试计划中的核心作用，我们已经开发了一个调查团队，以及丰富的资源和试剂，以实现该计划和PPTC的目标。在这里，我们建议使用一个大的（和不断增长的）收集PDX模型，已充分与最现代的基因组技术，以解决三个具体的研究目标。首先，我们将寻求利用我们最近的发现，即高危神经母细胞瘤在疾病复发时经常在ALK或MAPK信号通路的下游组分中携带激活突变。在这里，我们将开发组合疗法，不仅直接靶向通路，而且通过同时抑制PI 3 K-AKT通路来实现耐药的主要旁路机制。其次，我们将寻求通过溴结构域和末端外重复序列抑制剂与MAPK通路抑制剂的联合治疗靶向MYCN癌蛋白，MYCN癌蛋白是高危神经母细胞瘤中最具特征的致癌驱动因子。第三，我们将寻求利用这样一个事实，即主要肿瘤抑制基因如TP 53和RB 1的失活突变在神经母细胞瘤中是罕见的，并且将这些蛋白质捕获在细胞核中的治疗策略将协同增强由DNA损伤剂引起的细胞死亡。这些范例目标为基于证据和假设驱动的研究计划提供了路线图，该计划将通过PPTC指导委员会设定的优先事项，每年追求多达10个研究目标（临床前治疗试验）。PPTC内的神经母细胞瘤研究项目将通过进行关键的临床前研究来兑现生物标志物指导癌症治疗的承诺，这将大大提高我们设计早期临床试验的能力，为具有高受益潜力的患者提供丰富的内容。因此，该计划将寻求改变高风险神经母细胞瘤患者的治疗模式，其目标是在治愈率方面以及通过降低与当前护理标准相关的毒性来实质性改善结局。

 DESCRIPTION (provided by applicant): Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The long-term goal of our laboratory is to substantively improve neuroblastoma cure rates by developing patient-specific therapies that target the unique oncogenic drivers of each case. Within the context of the Pediatric Preclinical Testing Consortium (PPTC) we propose a Neuroblastoma Research Program built on richly annotated and highly characterized patient derived xenograft (PDX) and other murine models. The central hypothesis to be tested in this Program is that oncogenic drivers of neuroblastoma can be defined and exploited through rationally designed combinatorial therapies based on validated and clinically measurable biomarkers. Through our dedicated focus on neuroblastoma and our central role in the former Pediatric Preclinical Testing Program, we have developed an investigative team, and rich set of resources and reagents, to be uniquely positioned to achieve the goals of the Program and the PPTC. Here we propose to use a large (and growing) collection of PDX models that have been fully characterized with the most modern genomic technologies to address three specific research aims. First, we will seek to exploit our recent discovery that high-risk neuroblastoma frequently harbor activating mutations in ALK or downstream components of the MAPK signaling pathway at the time of disease relapse. Here we will develop combinatorial therapies that not only directly target the pathway, but also a major bypass mechanism of resistance by simultaneously inhibiting the PI3K-AKT pathway. Second, we will seek to target the MYCN oncoprotein, the most well characterized oncogenic driver in high-risk neuroblastoma, via combined therapy of a bromodomain and extra-terminal repeat inhibitor with an inhibitor of the MAPK pathway. Third, we will seek to take advantage of the fact that inactivating mutations in major tumor suppressor genes such as TP53 and RB1 are rare in neuroblastoma, and that therapeutic strategies to trap these proteins in the nucleus will synergistically enhance cell death caused by DNA damaging agents. These exemplar Aims provide a roadmap for an evidence-based and hypothesis-driven research Program that will be positioned to pursue up to 10 research aims (preclinical therapeutic trials) annually through priorities set by the PPTC steering committee. The Neuroblastoma Research Program within the PPTC will deliver on the promise of biomarker-directed therapeutics in cancer by performing the pivotal preclinical studies that will greatly enhance our ability to design early phase clinica trials enriched for patients with high potential to benefit. Thus, this Program will seek to shift he paradigm for how high-risk neuroblastoma patients are treated with the goal of substantively improving the outcomes, both in terms of cure rates, but also by decreasing the toxicity associated with current standards of care.