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

临床前-临床试验合作有效推进恶性周围神经鞘瘤的新联合疗法

• 批准号: 10393313
• 负责人: KAREN M CICHOWSKI
• 金额: $ 48.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393313
• 关键词: Affect; Animal Model; Applications Grants; Back; Basic Science; Biological; Biological Markers; Biology; Biopsy; Boston; Bromodomain; Cancer Biology; Cells; Chemotherapy and/or radiation; Child; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Collaborations; Combined Modality Therapy; Complement; Correlative Study; DNA Sequence Alteration; Data; Development; Developmental Therapeutics Program; Disease; District of Columbia; Dose; Enrollment; Epigenetic Process; Evaluation; Extramural Activities; Foundations; Future; Gene Expression Profile; Genomics; Goals; Grant; Hereditary Malignant Neoplasm; Hospitals; Human; Immune checkpoint inhibitor; Immunologics; Immunology; Immunotherapy; In Vitro; Individual; Industry; Infrastructure; Lead; MEKs; Malignant Neoplasms; Medical center; Modeling; Mus; Nature; Neoplasm Metastasis; Neurofibromatoses; Neurofibromatosis 1; Neurofibrosarcoma; Patient Outcomes Assessments; Patients; Pediatric Oncology; Phase I/II Clinical Trial; Phase I/II Trial; Phosphotransferases; Refractory; Refractory Disease; Relapse; Research Personnel; Research Project Grants; Resistance; Resources; Sampling; Schedule; Scientist; Series; Signal Transduction; Soft tissue sarcoma; Syndrome; Testing; Therapeutic; Time; Translating; Translational Research; Translations; United States National Institutes of Health; Unresectable; Woman; Work; anti-PD-L1 antibodies; base; bench to bedside; clinical application; clinical center; clinical translation; crizotinib; design; effective therapy; immunoreactivity; improved; in vivo; inhibitor; insight; mouse model; multidisciplinary; neoplasm immunotherapy; neoplasm resource; new combination therapies; novel; novel drug class; novel therapeutic intervention; novel therapeutics; open label; pharmacodynamic biomarker; phase 1 study; phase 2 study; pre-clinical; preclinical study; predicting response; prototype; resistance mechanism; response; response biomarker; sarcoma; small molecule inhibitor; standard of care; targeted treatment; therapeutic development; therapeutic target; therapy development; transcriptomics; translational scientist; tumor; tumor DNA; tumor microenvironment; tumorigenesis

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.

抽象的 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 相关的最常见致命特征是恶性周围神经鞘瘤 (MPNST)。 这些软组织肉瘤具有高度侵袭性并且经常转移。尽管有辐射和 化疗后，无法手术的肿瘤会迅速进展并且普遍致命。因此，识别有效的 MPNST 的治疗至关重要。 该应用程序的主要目标是建立强大的临床前/临床管道（实验室到床边和 返回）快速开发和测试针对这种致命恶性肿瘤的新（组合）疗法。这项努力将利用 NCI 和儿童国家医疗中心、校外临床研究人员的专业知识 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。具体来说，驱动 NF1 相关肿瘤发生机制的新发现以及最近的 对 MPNST 免疫反应性的深入了解将用于开发合理的联合疗法，并将 在强大的临床前 MPNST 小鼠模型（Karen Cichowski，BWH，校外临床前中心）中进行了测试。 然后，这些见解将用于对 MPNST 患者进行临床试验，重点是评估 同一试验中超过一种联合疗法（Brigitte Widemann，NCI，Intramural NIH 临床中心， AeRang Kim，国家儿童医疗中心）。这将有助于更及时地识别活性物质 并将让患有这种高度难治性疾病的患者有更多的治疗选择。 此外，临床前到临床的转化将得到全面的基因组和临床研究的补充。 对治疗前和新药治疗后获得的肿瘤样本进行免疫学分析 为了确定反应和抵抗机制并确定其他潜在的治疗目标 （Jack Shern，NCI，NIH 校内）。因此，来自诊所的见解和样本将作为基础 开发新的或改进现有的疗法，从而突出该管道的迭代和协作性质。 总而言之，我们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 MPNST 患者开发和转化有前景的疗法。这项工作包括 NF1 领域的专家 生物学和治疗开发，具有 MPNST 和免疫治疗专业知识的多元化临床医生， 和基因组学家。重要的是，这些研究人员中的一部分已经有合作记录 为 MPNST 患者开展新试验。这笔赠款将有助于更有效、更快速地转化有前景的成果 MPNST 的新疗法，并将扩大已开发的（联合）疗法的类型，通过引入 额外的专业知识并利用 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难治性肿瘤的护理标准 常见的家族性癌症综合征 NF1。