Developmental and Hyperactive Ras Tumor (DHART) SPORE

发育性和过度活跃 Ras 肿瘤 (DHART) 孢子

基本信息

批准号：
10494091
负责人：
David W Clapp
金额：
$ 213.95万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2015-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10494091
关键词：
Acute Myelocytic Leukemia Address Adolescent and Young Adult Affect Alleles Benefits and Risks Benign Binding Biological Markers Biological Response Modifier Therapy Cancer Biology Cell Lineage Central Nervous System Neoplasms Child Childhood Clinical Clinical Investigator Clinical Trials Core Facility Development Disease Funding GTPase-Activating Proteins Genetic Genetically Engineered Mouse Glioblastoma Goals Guanine Nucleotides Guanosine Triphosphate Hematopoietic Neoplasms High Prevalence Human Hydrolysis Incidence Inherited Juvenile Myelomonocytic Leukemia Learning Disabilities Lung Adenocarcinoma MEK inhibition Malignant Neoplasms Medical Molecular Analysis Morbidity - disease rate Mutation NF1 gene Neurofibromatosis 1 Neurofibrosarcoma Organ Orphan Output Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Physicians Pigments Plexiform Neurofibroma Population Pre-Clinical Model Premature Mortality Prevention Prognostic Marker Publications Research Personnel Resistance Risk Role Sampling Scientist Signal Transduction Syndrome Therapeutic Therapeutic Studies Tissues Translational Research Tumor Suppressor Genes Work acquired drug resistance base cancer predisposition cancer therapy comparative developmental disease driver mutation drug response prediction genome-wide hyperactive Ras improved outcome melanoma member molecular phenotype molecular targeted therapies mortality neoplastic next generation novel novel therapeutic intervention novel therapeutics patient derived xenograft model patient oriented preclinical trial predictive marker premalignant programs protein function rare cancer ras GTPase-Activating Proteins response risk stratification sarcoma skeletal dysplasia skin lesion targeted treatment translational cancer research translational scientist translational therapeutics treatment response tumor

项目摘要

ABSTRACT – OVERALL Neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome of a group of developmental disorders that are collectively termed “Rasopathies”. Germline NF1 mutations cause neurofibromatosis type 1 (NF1), a multi-system developmental disorder that is also the most common inherited cancer predisposition syndrome. NF1 is of exceptional importance in cancer biology because it encodes a GTPase activating protein (GAP) called neurofibromin that binds to active Ras-GTP and terminates signaling by accelerating guanine nucleotide hydrolysis. Thus, NF1 inactivation and somatic cancer-associated RAS mutations result in constitutively elevated Ras-GTP levels and aberrant activation of Ras-regulated kinase effector pathways in susceptible cell lineages. A markedly increased incidence of developing specific benign and malignant tumors is a hallmark of NF1 that results in substantial morbidity and mortality that affect children, adolescents, and young adults (AYAs) in a range of tissues. Investigating NF1-associated tumors represents a unique opportunity to interrogate therapeutic responses and mechanisms of intrinsic and acquired drug resistance in cancers that are initiated by a mutation that directly enhances Ras output. Given the central importance of aberrant Ras/GAP function in human cancer, and the emerging role of somatic NF1 mutations in common sporadic malignancies, achieving the goals of this SPORE will broadly advance translational cancer research and treatment. The overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPORE is to implement effective targeted therapies for neoplasms and cancers characterized by mutations in the NF1 tumor suppressor gene (TSG) by conducting integrated, mechanistically based translational research. The DHART SPORE deploys novel organizing principles and approaches to address the key challenge of how to accelerate new therapies for uncommon (“orphan”) benign and malignant tumors across an organ spectrum with a common driver mutation. The DHART SPORE is comprised of a highly integrated group of translational scientists that are addressing central issues for implementing mechanism-based treatments for rare tumors driven by hyperactive Ras signaling in the pediatric, adolescent, and young adult (AYA) population. Across all three projects, state-of-the-art core facilities will inform the patient-oriented therapeutic and prevention aspects by delineating mutations that contribute to cancer pathogenesis, and by uncovering new biomarkers of drug response and resistance that will inform the development of “next generation” treatments. Achieving the objectives of the proposed Projects 1-3 will not only improve the outcomes of NF1 and non-NF1 patients with specific cancers but has the potential to inform new therapeutic approaches for the substantial proportion of human cancers characterized by somatic NF1 and RAS mutations that have implications for enhancing the treatment of the ~1/3rd of all cancers with somatic RAS mutations.

摘要 - 总体 1型神经纤维瘤病（NF1）是最常见的遗传癌症易感综合征统称为“ rasopathies”的一群发育障碍。种系NF1突变导致神经纤维瘤病1型（NF1），一种多系统发育障碍，也是最常见的遗传癌症易感综合征。 NF1在癌症生物学中至关重要，因为它编码了 GTPase激活蛋白（GAP）称为神经纤维蛋白，与活性Ras-GTP结合并终止信号传导通过加速鸟嘌呤核丁基水解。那是NF1失活和与体细胞癌相关的RA 突变导致组成性升高的Ras-GTP水平和RAS调节激酶的异常激活易感细胞谱系中的效应途径。开发特定良性的发生率明显增加恶性肿瘤是NF1的标志，导致影响很大的发病率和死亡率在一系列组织中的儿童，青少年和年轻人（AYA）。研究NF1相关的肿瘤代表了询问固有的治疗反应和机制的独特机会，并获得了通过直接增强RAS输出的突变引发的癌症中的耐药性。给定中心异常RAS/GAP功能在人类癌症中的重要性以及体细胞NF1突变的新兴作用常见的零星恶性肿瘤，实现这一孢子的目标将广泛促进转化癌症研究和治疗。这种发育和多动性RAS肿瘤（DHART）孢子的总体目标是针对以NF1突变为特征的肿瘤和癌症实施有效的靶向疗法肿瘤抑制基因（TSG）通过进行基于机械的综合转化研究。这 Dhart Spore部署了新颖的组织原理和方法，以应对如何加速不常见（“孤儿”）良性和恶性肿瘤的新疗法带有常见的驱动器突变。 Dhart孢子由一组高度集成的翻译组组成正在解决针对稀有肿瘤实施基于机制治疗的中心问题的科学家由小儿，青少年和年轻人（AYA）人群中的多动性RAS信号传导驱动。总体上三个项目，最先进的核心设施将为以患者为导向的理论和预防方面提供信息通过描述有助于癌症发病机理的突变，并发现了新的药物生物标志物响应和抵抗力将为“下一代”治疗的发展提供依据。实现拟议项目1-3的目标不仅会改善NF1和非NF1患者的结果特定的癌症，但有可能告知新的治疗方法以体细胞NF1和RAS突变为特征的人类癌症对增强具有影响所有具有体细胞RAS突变的癌症的〜1/3的处理。