Developing a translational pipeline for NF1-mutant malignancies

 描述(申请人提供)：神经纤维瘤病1型(NF1)是一种流行的家族性癌症综合征，全世界每3500人中就有1人受到影响。与NF1相关的最常见的致命特征是恶性周围神经鞘瘤(MPNST)。这些软组织肉瘤侵袭性很强，经常转移。尽管有放疗和化疗，但无法手术的肿瘤进展迅速，而且普遍是致命的。因此，确定MPNST的有效治疗方法至关重要。这项应用的主要目标是建立一个强大的临床前/临床管道(从床边到床边和床后)，以快速开发和测试这种致命恶性肿瘤的新(组合)疗法。这项工作将利用NCI和儿童国家医学中心的临床研究人员、NF1生物学和治疗开发方面的外部专家的专业知识，并将利用NIH临床中心的独特资源。具体地说，推动NF1相关肿瘤发生机制的新发现以及对MPNST免疫反应性的最新见解将被用于开发合理的组合疗法，并将在强大的临床前MPNST小鼠模型(Karen Cichowski，BWH，壁外临床前中心)中进行测试。这些见解随后将被用于对MPNST患者进行临床试验，重点是评估同一试验中的一种以上联合疗法。这将允许更及时地识别活性物质，并使这种高度难治性疾病的患者有更多的治疗选择可供他们使用(Brigitte Widemann，NCI，校内临床中心)。此外，临床前向临床的转化将通过对治疗前和新药治疗时获得的肿瘤样本进行全面的基因组和免疫学分析来补充，以确定反应和耐药性的机制，并确定个别患者的其他潜在治疗靶点。因此，来自诊所的洞察力和样本将作为开发新的或改进现有疗法的基础，从而突出这一渠道的迭代和合作性质。综上所述，我们已经组建了一个由来自不同领域的基础和临床科学家组成的多学科团队，为MPNST患者开发和翻译有前途的疗法。这项工作包括NF1生物学和治疗开发方面的专家、癌症免疫生物学家、具有MPNST和免疫疗法专业知识的不同临床医生以及基因学家。重要的是，这些研究人员中的一部分已经有过合作为MPNST患者开发新试验的记录。这笔赠款将使MPNST有希望的新疗法能够更有效和更快地转化，并将通过引入更多的专业知识和利用临床中心的独特资源来扩大所开发的(组合)疗法的类型。最终，这些研究有可能改变目前治疗与常见家族性癌症综合征NF1相关的难治性肿瘤的护理标准。

 DESCRIPTION (provided by applicant): Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome affecting 1 in 3500 individuals worldwide. The most commonly lethal feature associated with NF1 is malignant peripheral nerve sheath tumors (MPNST). These soft tissue sarcomas are highly aggressive and frequently metastasize. Despite radiation and chemotherapy, inoperable tumors rapidly progress and are universally lethal. As such, identifying effective treatments for MPNST is critical. The primary goal of this application is to establish a robust preclinical/clinical pipeline (bench-to-bedside and back) to rapidly develop and test new (combination) therapies for this deadly malignancy. This effort will harness the specialized expertise of clinical investigators at the NCI and Children's National Medical Center, extramural experts in NF1 biology and therapeutic development, and will leverage the unique resources of the NIH Clinical Center. Specifically, new discoveries of mechanisms that drive NF1-related tumorigenesis together with recent insights into the immunoreactivity of MPNST will be used to develop rational combination therapies and will be tested in a robust preclinical MPNST mouse model (Karen Cichowski, BWH, extramural preclinical center). These insights will then be used to perform clinical trials in MPNST patients with an emphasis on evaluating more than one combination therapy within the same trial. This will allow for more timely identification of active agents, and allow patients with this highly refractory disease to have mor treatment options available to them (Brigitte Widemann, NCI, intramural clinical center). Furthermore, the preclinical to clinical translation will be complemented by comprehensive genomic and immunological analyses of tumor samples obtained prior to treatment and on treatment with novel agents in order to identify mechanisms of response and resistance and to identify additional potential targets for therapy in individual patients. As such, insight and samples from the clinic will serve as the foundation to develop new or improve existing therapies, thus highlighting the iterative and collaborative nature of this pipeline. Taken togethe, we have assembled a multi-disciplinary team of basic and clinical scientists from different fields to develop and translate promising therapies for individuals with MPNST. This effort includes experts in NF1 biology and therapeutic development, cancer immunobiologists, a diverse set of clinicians with expertise in MPNST and immunotherapy, and genomicists. Importantly, a subset of these investigators already have a track record of working together to develop new trials for MPNST patients. This grant will allow more effective and rapid translation of promising new therapies for MPNST, and will expand the type of (combination) therapies that are developed, by bringing in additional expertise and leveraging the unique resources of the Clinical Center. Ultimately, these studies have the potential to change the standard of care for the currently treatment refractory tumors associated with the common familial cancer syndrome NF1.