Preclinical-Clinical Trials Collaboration to effectively advance new combination therapies for malignant peripheral nerve sheath tumors

摘要 1型神经纤维瘤病(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。尽管有辐射和 化疗后，不能手术的肿瘤进展迅速，而且普遍致命。因此，确定有效的 MPNST的治疗至关重要。 该应用程序的主要目标是建立一个强大的临床前/临床管道(床到床和 快速开发和测试这种致命恶性肿瘤的新(组合)疗法。这一努力将使 NCI和国家儿童医学中心临床研究人员的专业知识，校外 NF1生物学和治疗开发方面的专家，并将利用NIH临床的独特资源 中心。具体地说，推动NF1相关肿瘤发生的机制的新发现与最近的 对MPNST免疫反应性的洞察将被用于开发合理的联合疗法，并将 在强健的临床前MPNST小鼠模型(Karen Cichowski，BWH，壁外临床前中心)中进行了测试。 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治疗(Brigitte Widemann，NCI，Intral NIH临床中心， AeRang Kim，国家儿童医学中心。这将允许更及时地识别活动代理 并将使这种高度难治性疾病的患者有更多的治疗选择。 此外，临床前到临床的转换将得到全面的基因组和 新药治疗前后肿瘤标本的免疫学分析 以确定反应和耐药性的机制，并确定其他潜在的治疗靶点 (杰克·谢恩，NCI，NIH内部)因此，诊所的洞察力和样本将作为基础 开发新的或改进现有的治疗方法，从而突出这一管道的迭代和协作性质。 总而言之，我们已经组建了一支由来自不同领域的基础和临床科学家组成的多学科团队 为患有MPNST的患者开发和翻译有前景的治疗方法。这项工作包括NF1的专家 生物学和治疗发展，拥有MPNST和免疫疗法专业知识的不同临床医生组， 和基因学家。重要的是，这些调查人员中的一部分已经有过合作的记录 为MPNST患者开发新的试验。这笔赠款将使Promising的翻译更加有效和快速 MPNST的新疗法，并将通过引入 更多的专业知识和利用NIH临床中心的独特资源。最终，这些研究 有可能改变目前治疗的难治性肿瘤的护理标准 常见的家族性癌综合征NF1。

ABSTRACT 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 (Brigitte Widemann, NCI, Intramural NIH Clinical Center, AeRang Kim, Children’s National Medical Center). This will allow for more timely identification of active agents and will allow patients with this highly refractory disease to have more treatment options available to them. 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 (Jack Shern, NCI, Intramural NIH). 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 together, 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, 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 NIH 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.