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) 是最常见的遗传性癌症易感综合征一组统称为“Rasopathies”的发育障碍。 1 型神经纤维瘤病 (NF1)，一种多系统发育障碍，也是最常见的遗传性疾病 NF1在癌症生物学中具有特殊的重要性，因为它编码一个 GTP 酶激活蛋白 (GAP) 称为神经纤维蛋白，可与活性 Ras-GTP 结合并终止信号传导通过加速鸟嘌呤核苷酸水解，NF1失活和体细胞癌相关的RAS。突变导致 Ras-GTP 水平持续升高以及 Ras 调节激酶的异常激活易感细胞谱系中的效应途径显着增加发生特定良性的发生率。恶性肿瘤是 NF1 的一个标志，它会导致大量的发病率和死亡率，影响研究 NF1 相关肿瘤的儿童、青少年和年轻人 (AYA)。代表了一个独特的机会来询问内在和后天的治疗反应和机制癌症中的耐药性是由直接增强 Ras 输出的突变引发的。 Ras/GAP 功能异常在人类癌症中的重要性，以及体细胞 NF1 突变在癌症中的新作用常见的散发性恶性肿瘤，实现该 SPORE 的目标将广泛促进转化癌症发育性和过度活跃 Ras 肿瘤 (DHART) 孢子的研究和治疗的总体目标。旨在针对以 NF1 突变为特征的肿瘤和癌症实施有效的靶向治疗通过进行综合的、基于机制的转化研究来抑制肿瘤抑制基因（TSG）。 DHART SPORE 部署新颖的组织原则和方法来解决如何加速针对整个器官范围内罕见（“孤儿”）良性和恶性肿瘤的新疗法 DHART SPORE 由一组高度集成的翻译组成。正在解决针对罕见肿瘤实施基于机制的治疗的核心问题的科学家由儿科、青少年和青年 (AYA) 人群中过度活跃的 Ras 信号驱动。三个项目，最先进的核心设施将为以患者为中心的治疗和预防方面提供信息通过描述导致癌症发病机制的突变，并发现新的药物生物标志物反应和耐药性将为“下一代”治疗的开发提供信息。拟议项目 1-3 的目标不仅会改善 NF1 和非 NF1 患者的治疗结果特定癌症，但有可能为大部分癌症提供新的治疗方法以体细胞 NF1 和 RAS 突变为特征的人类癌症，这些突变对增强治疗约 1/3 的具有体细胞 RAS 突变的癌症。