Developmental and HyperActive Ras Tumor SPORE

描述（由申请人提供）：1型神经纤维瘤病（NF1）是最常见的遗传性癌症易感性综合征，全球发病率为1 / 3000。NF1是由NF1肿瘤抑制基因（TSG）的种系突变引起的，该基因编码一种称为神经纤维蛋白的GTPase激活蛋白（GAP），与活化的Ras-GTP形成分子复合物，并通过加速GTP水解来负性调节Ras信号传导。NF1是最常见的皮肤病变，有发展为恶性肿瘤的倾向，常影响儿童、青少年和年轻人。NF1相关肿瘤和恶性肿瘤的一个共同特征是正常NF1等位基因的体细胞缺失。重要的是，有限的流行病学数据支持这样的假设，即原发性癌症治愈的NF1患者发生治疗性继发性肿瘤（SNs）的风险增加。总之，NF1中发生的肿瘤疾病和侵袭性恶性肿瘤是发病率和过早死亡的重要原因。除了在NF1相关癌症中作为起始突变的作用外，最近的全基因组测序研究发现，在胶质母细胞瘤、急性髓性白血病、肺腺癌和其他散发性癌症中，NF1经常发生体细胞突变。重要的是，对于编码Ras/GAP分子开关组分（KRAS， NRAS， HRAS和NF1）的基因突变的癌症，目前没有基于机制的治疗方法。因此，我们的重点将是为患有神经纤维瘤病（NF）的儿童、青少年和年轻人开发有效的高质量医疗保健服务方案，并提供将使整个Ras社区受益的见解。这个发育和多活性Ras肿瘤（DHART）孢子的总体目标是通过进行综合的、基于机制的转化研究，实现肿瘤和癌症的有效靶向分子治疗。这个高素质的合作小组的总体目标是：1)在经过验证的临床前模型和NF1患者的治疗中评估新的治疗方法；2)确定NF1患者获得自发性和治疗相关的第二恶性肿瘤的危险因素；3)降低NF1患者的肿瘤相关发病率和死亡率。该应用程序借鉴了临床研究人员、医生/科学家和基础研究人员的专业知识，具有广泛的生产性合作记录。该项目包括四个高度整合的项目和三个核心。项目1到项目3的主题是转化治疗学，项目4的重点是癌症流行病学和预防的作用。最先进的核心设施将通过阐明导致癌症发病机制的突变，以及通过定义药物反应和耐药性的生物标志物，为“下一代”治疗提供信息，从而为该孢子的患者导向的癌症治疗和预防方面提供信息。

DESCRIPTION (provided by applicant): With a worldwide incidence of 1 in 3000, neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome. NF1 is caused by germ line mutations in the NF1 tumor suppressor gene (TSG), which encodes a GTPase activating protein (GAP) called neurofibromin that forms a molecular complex with activated Ras-GTP and negatively regulates Ras signaling by accelerating GTP hydrolysis. NF1, the most common rasopathy, has a propensity to develop neoplastic diseases that progress to aggressive cancers and frequently affect children, adolescents, and young adults. A common feature of NF1-associated neoplasms and malignant tumors is somatic loss of the normal NF1 allele. Importantly, limited epidemiologic data support the hypothesis that patients with NF1 who are cured of a primary cancer are at increased risk of developing treatment-induced secondary neoplasms (SNs). Together, the neoplastic diseases and aggressive malignancies that develop in NF1 are a substantial cause of morbidity and premature mortality. In addition to its role as an initiating mutation in NF1-associated cancers, recent genome-wide sequencing studies uncovered frequent somatic NF1 mutations in glioblastoma, acute myeloid leukemia, adenocarcinoma of the lung, and other sporadic cancers. Importantly, there are currently no mechanism-based therapies for cancers with mutations in genes encoding components of the Ras/GAP molecular switch (KRAS, NRAS, HRAS, and NF1). Thus, our focus will be developing effective higher-quality healthcare delivery options for children, adolescents and young adults with neurofibromatosis (NF) and provide insights that will benefit the entire Ras community. The overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPORE is to implement effective targeted molecular therapies for neoplasms and cancers by conducting integrated, mechanistically based translational research. The overarching objectives of this highly-qualified, collaborative group are : 1) to evaluate novel therapeutics in validated preclinical models and in the treatment of patients with NF1; 2) to identify risk factors of individuals with NF1 to acquire spontaneous and treatment-associated second malignancies; and 3) to decrease tumor associated morbidity and mortality of patients with NF1. This application draws on the expertise of an accomplished team of clinical investigators, physician/ scientists, and basic researchers with an extensive track record of productive collaborations. This program encompasses four highly integrated projects and three cores. The theme of translational therapeutics informs Projects 1 through 3, and the focus of project 4 exemplifies the role of cancer epidemiology and prevention. State-of-the-art core facilities will inform the patient-oriented cancer therapeutic and prevention aspects of this SPORE by elucidating mutations that contribute to of cancer pathogenesis and by defining biomarkers of drug response and resistance that will inform "next generation" treatments.