Proj 1 - Targeting Evolving Therapy Resistance

项目 1 - 针对不断变化的治疗耐药性

• 批准号: 10265472
• 负责人: Yael P Mosse
• 金额: $ 32.02万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265472
• 关键词: Address; Adult; Architecture; Attention; Biological Assay; Biological Markers; Case Series; Chemoresistance; Child; Clinic; Clinical; Combined Modality Therapy; Complex; Custom; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; Drug Interactions; Etiology; Frequencies; Genes; Genetic; Genetic Heterogeneity; Genome; Genomics; Goals; Health; Heterogeneity; Human; Immunotherapy; Intervention; Knowledge; Left; Life; MAP Kinase Gene; MEK inhibition; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Mission; Modeling; Modernization; Molecular; Monitor; Motivation; Mutation; Neuroblastoma; Newly Diagnosed; Oncogenes; Oncogenic; Oncoproteins; PTK2 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatrics; Population; Positioning Attribute; Public Health; Publishing; Receptor Protein-Tyrosine Kinases; Recurrent disease; Relapse; Research; Resistance; Role; Sampling; Series; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Solid Neoplasm; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; United States National Institutes of Health; Work; base; chemoradiation; chemotherapeutic agent; childhood cancer mortality; clinically significant; cohort; combinatorial; deep sequencing; disorder risk; driver mutation; evidence base; gain of function mutation; high risk; improved; improved outcome; inhibitor/antagonist; melanoma; molecular targeted therapies; neoplastic cell; next generation; novel; novel therapeutics; patient derived xenograft model; pre-clinical; preclinical trial; pressure; prevent; programs; sequencing platform; side effect; subclonal heterogeneity; success; targeted agent; targeted treatment; therapy resistant; tumor; tumor heterogeneity; tumorigenesis

SUMMARY/ABSTRACT Neuroblastoma (NB) remains a leading cause of childhood cancer deaths, and the children who do survive are left with long-term side effects, many of which can be life threatening. In this era of more precise therapies, considerable efforts are being made to identify optimal targets. While the paradigm of molecularly targeted therapies holds great promise, genomic studies have revealed that NBs are characterized by extensive intratumor genetic heterogeneity, with subclonal oncogenic drivers often selected for during standard chemoradiotherapy. Our group discovered gain-of-function mutations in the ALK receptor tyrosine kinase as the etiology for familial NB, and at the same time co-discovered with several other groups identical mutations as the most frequent somatic single nucleotide variants leading to a potent oncogenic driver in up to 15% of newly diagnosed high-risk cases. Our more recent work has shown that activating mutations in the ALK-RAS- MAPK pathway are highly enriched in the relapse NB genome, providing the impetus for deep and comprehensive characterization of the subclonal landscape of genes within these pathways across the continuum of therapy. This serves at the motivation for this Project and provides the opportunity to both adapt therapeutic approaches as tumors evolve, and also target subclonal mutations earlier to prevent the acquisition of chemotherapy resistant dominant clones. The central hypothesis to be explored here is that high-risk NBs are characterized by extensive intratumoral and stroma-derived heterogeneity and harbor pre-existing and acquired subclonal populations that confer therapy resistance that can exploited with rationally selected targeted agents. We will test our central hypothesis in three Specific Aims: 1) Define the frequency and clinical significance of subclonal driver mutations; 2) Identify therapeutic vulnerabilities imparted by inhibition of oncogenic ALK and/or RAS-MAPK signaling; 3) Target tumor cell intrinsic and extrinsic oncogenic vulnerabilities for development of rational novel therapeutics. The first Aim will employ a custom ultra-deep sequencing platform to define the clonal and subclonal architecture and mutational landscape in diagnostic and relapse NBs, including PDX models. Aim 2 is devoted to defining therapeutically exploitable oncogenic vulnerabilities with a focus on demonstrating that inhibition of FAK leads to robust anti-tumor activity in ALK- and RAS-driven NBs treated with inhibitors of these pathways. The final Aim will garner the preclinical justification required to move combination therapies to the clinic, building on our extensive preliminary data of synergistic drug interactions in our oncogene-driven models. We consider this project significant because it will result in new mechanism-based biomarker-defined therapeutic strategies that ultimately should significantly improve high-risk NB patient outcomes. This will address the major unmet need that despite unprecedented discoveries in defining the basic mechanisms of NB tumorigenesis, this knowledge has not yet translated into significantly improved outcomes for patients with high-risk disease.

总结/摘要 神经母细胞瘤（NB）仍然是儿童癌症死亡的主要原因，存活的儿童是 留下长期的副作用，其中许多可能危及生命。在这个更精确治疗的时代， 目前正在作出相当大的努力，以确定最佳目标。虽然分子靶向治疗的范例 基因组研究表明，NBs的特征是广泛的 肿瘤内遗传异质性，亚克隆致癌驱动因子通常在标准治疗期间选择 放化疗我们的研究小组发现ALK受体酪氨酸激酶的功能获得性突变， 病因为家族性NB，同时发现与其他几组相同的突变 作为最常见的体细胞单核苷酸变异，导致高达15%的 新诊断的高危病例。我们最近的研究表明，ALK-RAS-1中的激活突变， MAPK通路在复发NB基因组中高度富集，为复发NB的深层和深层治疗提供了动力。 这些途径中基因的亚克隆景观的全面表征， 连续治疗。这是本项目的动机，并提供了适应的机会， 随着肿瘤的发展，治疗方法也会更早地靶向亚克隆突变，以防止获得 对化疗有抵抗力的显性克隆这里要探讨的中心假设是，高风险NB 特征在于广泛的瘤内和基质来源的异质性， 获得的亚克隆群体赋予了治疗抗性，可以通过合理选择来利用这些亚克隆群体。 目标代理人我们将在三个具体目标中测试我们的中心假设：1）定义频率和临床 亚克隆驱动突变的重要性; 2）鉴定通过抑制 致癌ALK和/或RAS-MAPK信号传导; 3）靶向肿瘤细胞内在和外在致癌 开发合理的新疗法的脆弱性。第一个目标将采用定制的超深 测序平台，以确定诊断和治疗中的克隆和亚克隆结构以及突变景观， 复发NB，包括PDX模型。目标2致力于定义治疗上可利用的致癌基因 重点是证明FAK的抑制导致ALK中的稳健抗肿瘤活性， 和用这些途径的抑制剂处理的RAS驱动的NB。最终目标将获得临床前 根据我们广泛的初步数据， 协同药物相互作用在我们的致癌基因驱动的模型。我们认为这个项目很重要，因为它将 导致新的机制为基础的生物标志物定义的治疗策略，最终应显着 改善高风险NB患者结局。这将解决尽管前所未有， 尽管在定义NB肿瘤发生的基本机制方面有一些发现，但这些知识尚未转化为 显著改善高危疾病患者的预后。