Developmental and Hyperactive Ras Tumor (DHART) SPORE

摘要-总体 1型神经纤维瘤病（NF 1）是一种最常见的遗传性癌症易感综合征， 一组发育障碍，统称为“Rasopathies”。种系NF 1突变导致 1型神经纤维瘤病（NF 1）是一种多系统发育障碍，也是最常见的遗传性疾病。 癌症易感综合征NF 1在癌症生物学中具有特殊的重要性，因为它编码一种 GTP酶激活蛋白（GAP），称为神经纤维蛋白，与活性Ras-GTP结合并终止信号传导 通过加速鸟嘌呤核苷酸水解。因此，NF 1失活和体细胞癌相关RAS 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 易感细胞系中的效应子途径。一个明显增加的发病率发展特定的良性 和恶性肿瘤是NF 1的标志，其导致大量的发病率和死亡率， 儿童、青少年和年轻人（AYA）在一系列组织中。研究NF 1相关肿瘤 代表了一个独特的机会，询问治疗反应和机制的内在和后天的 癌症中的耐药性是由直接增强Ras输出的突变引发的。鉴于中央 Ras/GAP功能异常在人类癌症中的重要性，以及体细胞NF 1突变在 常见的散发性恶性肿瘤，实现本SPORE的目标将广泛推进转化癌 研究和治疗。这个发展和过度活跃的Ras肿瘤（DHART）孢子的总体目标 是对以NF 1突变为特征的肿瘤和癌症实施有效的靶向治疗， 肿瘤抑制基因（TSG）进行整合，机制为基础的翻译研究。的 DHART SPORE部署了新颖的组织原则和方法来解决如何 加速器官谱中罕见（“孤儿”）良性和恶性肿瘤的新疗法 有共同的驱动基因突变DHART孢子由一组高度整合的翻译 科学家们正在解决对罕见肿瘤实施基于机制的治疗的核心问题， 由儿童、青少年和年轻成人（AYA）人群中过度活跃的Ras信号传导驱动。跨所有 三个项目，最先进的核心设施将告知以病人为导向的治疗和预防方面 通过描绘有助于癌症发病机制的突变，并通过发现新的药物生物标志物， 反应和耐药性，这将为“下一代”治疗的发展提供信息。实现 拟议项目1-3的目标不仅将改善NF 1和非NF 1患者的结局， 特定的癌症，但有可能告知新的治疗方法的相当大的比例， 以体细胞NF 1和RAS突变为特征的人类癌症， 治疗约1/3的具有体细胞RAS突变的癌症。

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.