Developing a translational pipeline for NF1-mutant malignancies

开发 NF1 突变恶性肿瘤的转化管道

• 批准号: 9038698
• 负责人: KAREN M CICHOWSKI
• 金额: $ 57.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038698
• 关键词: Affect; Back; Biological; Biology; Biopsy; Blood specimen; Cancer Biology; Cells; Child; Clinic; Clinical; Clinical Investigator; Clinical Trials; Clinical Trials Design; Collaborations; Combined Modality Therapy; Comparative Study; Complement; DNA Sequence Alteration; Data; Development; Disease; Evaluation; Extramural Activities; Foundations; Genetic; Genomics; Goals; Grant; Hereditary Malignant Neoplasm; Human; Immune; Immune response; Immunologic Markers; Immunology; Immunotherapeutic agent; Immunotherapy; Individual; Laboratories; MEK inhibition; Maintenance; Malignant Neoplasms; Medical center; Metastatic Malignant Peripheral Nerve Sheath Tumor; Modeling; Molecular Profiling; Mus; Nature; Neoplasm Metastasis; Neurofibromatosis 1; Neurofibrosarcoma; Pathway interactions; Patients; Population; Pre-Clinical Model; Radiation; Refractory; Refractory Disease; Regulation; Research Personnel; Research Project Grants; Resistance; Resources; Sampling; Scientist; Signal Transduction; Soft tissue sarcoma; Specific qualifier value; Syndrome; T cell response; Testing; Therapeutic; Translating; Translational Research; Translations; United States National Institutes of Health; Unresectable; Validation; Work; base; bench to bedside; cancer genomics; chemotherapy; clinical application; clinical infrastructure; comparative; effective therapy; epigenetic profiling; exome sequencing; experience; fluorodeoxyglucose positron emission tomography; imaging biomarker; immunogenic; immunoreactivity; immunoregulation; improved; individual patient; insight; killings; mTOR inhibition; model development; mouse model; mutant; neoplasm immunotherapy; new combination therapies; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; phase II trial; pre-clinical; preclinical study; public health relevance; response; sarcoma; small molecule inhibitor; standard of care; targeted treatment; therapeutic development; therapy resistant; transcriptome sequencing; treatment response; trial design; tumor; tumor growth; tumorigenesis

 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.

 描述（由适用提供）：1型神经纤维瘤病（NF1）是一种普遍的家族癌综合征，影响了全球3500人中有1个。与NF1相关的最常见的致命特征是恶性周围神经护套肿瘤（MPNST）。这些软组织肉瘤是高度​​侵略性的，并且经常转移。尽管放疗和化学疗法，但无法手术的肿瘤迅速进展，并且是普遍致命的。因此，确定MPNST的有效治疗是至关重要的。该应用程序的主要目标是建立强大的临床前/临床管道（基准对床和背部），以快速开发和测试这种致命的恶性肿瘤的新（组合）疗法。这项工作将利用NCI和儿童国家医学中心，NF1生物学和治疗开发的壁外专家的临床研究人员的专业知识，并将利用NIH临床中心的独特资源。具体而言，驱动NF1相关肿瘤发生的机制的新发现以及对MPNST的免疫反应性的最新见解将用于开发合理组合疗法，并将在鲁棒的临床前MPNST小鼠模型（Karen Cichowski，bwhowski，bwwh，bwh，bwh，bwh，bwhermural teramural preclinical Center）中进行测试。然后，这些见解将用于在MPNST患者中进行临床试验，重点是在同一试验中评估多种组合疗法。这将允许对活性药物进行更及时的识别，并允许患有这种高度难治性疾病的患者可以使用MOR治疗选择（Brigitte Widemann，NCI，NCI，壁内临床中心）。此外，临床翻译的临床前翻译将通过在治疗前和新型药物治疗后获得的综合基因组和免疫学分析来完成，以识别反应和抗性的机制，并确定单个患者治疗的其他潜在靶标。因此，诊所的洞察力和样本将作为开发新或改善现有疗法的基础，从而突出该管道的迭代和协作性质。采取行动，我们组建了一个来自不同领域的基本和临床科学家组成的多学科团队，以开发和翻译MPNST个人的疗法。这项工作包括NF1生物学和治疗发展方面的专家，癌症免疫生物学家，一组潜水员在MPNST和免疫疗法方面具有专业知识的临床医生以及基因组医生。重要的是，这些研究人员的一部分已经有了共同努力为MPNST患者开发新试验的记录。该赠款将使Promist for MPNST的新疗法更有效，更快地翻译，并通过引入更多专业知识并利用临床中心的独特资源来扩展开发的（组合）疗法的类型。最终，这些研究有可能改变与普通家庭癌症综合征NF1相关的当前治疗难治性肿瘤的护理标准。