Pediatric Preclinical Testing Consortium

儿科临床前测试联盟

基本信息

批准号：
9107415
负责人：
JOHN M MARIS
金额：
$ 35.7万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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/9107415
关键词：
Accounting Address Adriamycin PFS Basic Science Biological Markers Bromodomain Bypass Caring Cell Death Cell Nucleus Cessation of life Child Childhood Chromatin Clinical Clinical Trials Collaborations Collection DNA Damage Data Development Diagnosis Disease Drug Combinations Drug Interactions Effectiveness Family Future Genetic Genomics Goals Health Immunotherapy Industry Laboratories Lesion MAP Kinase Gene MAP2K1 gene MAPK Signaling Pathway Pathway MEK inhibition MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Measurable Methods Mission Mitogen-Activated Protein Kinase Inhibitor Morbidity - disease rate Motivation Mutation Neuroblastoma Newly Diagnosed Nuclear Export Nuclear Protein Oncogenes Oncogenic Outcome PI3K/AKT Pathway interactions Patients Pediatric Neoplasm Pediatric Oncology Peripheral Pharmaceutical Preparations Phase Positioning Attribute Pre-Clinical Model Preclinical Drug Development Preclinical Testing Protein Inhibition Proteins Proto-Oncogene Proteins c-akt Public Health Publishing RB1 gene Radiation therapy Reader Reagent Recurrent disease Refractory Relapse Research Resistance Resources Role Sympathetic Nervous System TP53 gene Technology Terminal Repeat Sequences Testing Therapeutic Therapeutic Trials Thinking Time Toxic effect Translating Translational Research Treatment Failure Tumor Suppressor Genes Tumor Suppressor Proteins United States National Institutes of Health Work Xenograft Model Xenograft procedure anticancer research base biomarker-driven cell killing chemotherapy childhood cancer mortality combinatorial design evidence base exportin 1 protein high risk improved improved outcome inhibitor/antagonist mortality mouse model novel novel therapeutics pre-clinical pre-clinical research preclinical study programs resistance mechanism screening standard of care targeted treatment therapy development tumor

项目摘要

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.

描述（由申请人提供）：尽管接受强化化疗、放射治疗和免疫治疗，患有播散性神经母细胞瘤的儿童仍有很高的治疗失败和死亡风险。在儿科临床前测试联盟 (PPTC) 的背景下，我们提出了一项基于每个病例独特致癌驱动因素的特定疗法。该计划要测试的中心假设是，可以通过基于经过验证的临床可测量生物标志物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。我们专注于神经母细胞瘤以及我们在前儿科临床前测试项目中的核心作用，我们已经建立了一个研究团队以及丰富的资源和试剂，以独特的方式实现该计划和 PPTC 的目标。在此，我们建议使用大量（且不断增长的）PDX 模型，这些模型已通过最现代的基因组技术进行了充分表征，以解决三个特定的研究目标。首先，我们将寻求利用我们最近的发现，即在疾病复发时，高风险神经母细胞瘤经常含有 ALK 或 MAPK 信号通路下游成分的激活突变。在这里，我们将开发不仅直接针对该通路的组合疗法。但其次，我们将寻求通过溴结构域和末端重复序列的联合治疗来靶向 MYCN 癌蛋白，这是高风险神经母细胞瘤中最明确的致癌驱动因素。第三，我们将寻求利用主要肿瘤抑制基因（例如 TP53 和 RB1）的失活突变在神经母细胞瘤中罕见的事实。这些示例目标为基于证据和假设驱动的研究计划提供了路线图，该计划将致力于实现多达 10 个研究目标。（临床前治疗试验）每年根据 PPTC 指导委员会确定的优先事项进行，PPTC 内的神经母细胞瘤研究计划将通过进行关键的临床前研究来兑现以生物标志物为导向的癌症治疗的承诺。极大地增强我们为具有高获益潜力的患者设计丰富的早期临床试验的能力，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，以期实质性改善结果。治愈率，而且还通过降低与当前护理标准相关的毒性。