Proj 1 - Targeting Evolving Therapy Resistance

项目 1 - 针对不断变化的治疗耐药性

• 批准号: 10017934
• 负责人: Yael P Mosse
• 金额: $ 30.28万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017934
• 关键词: Address; Adult; Architecture; Attention; Biological Assay; Biological Markers; Case Series; 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; Xenograft Model; base; chemoradiation; chemotherapeutic agent; chemotherapy; 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; 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.

摘要/摘要 神经母细胞瘤 (NB) 仍然是儿童癌症死亡的主要原因，而幸存下来的儿童是 留下长期副作用，其中许多可能危及生命。在这个更加精准治疗的时代， 正在付出巨大努力来确定最佳目标。虽然分子靶向的范式 疗法前景广阔，基因组研究表明，NBs 的特点是广泛 肿瘤内遗传异质性，在标准过程中通常选择亚克隆致癌驱动因素 放化疗。我们的小组发现 ALK 受体酪氨酸激酶的功能获得性突变为 家族性NB的病因，同时与其他几个群体共同发现了相同的突变 作为最常见的体细胞单核苷酸变异，可在高达 15% 的癌症中产生有效的致癌驱动因素 新确诊的高危病例。我们最近的工作表明，激活 ALK-RAS 中的突变 MAPK 通路在复发 NB 基因组中高度富集，为深入和治疗提供动力。 这些途径中基因亚克隆景观的综合表征 治疗的连续性。这是该项目的动力，并提供了适应的机会 随着肿瘤的发展而采取治疗方法，并尽早针对亚克隆突变以防止获得 化疗耐药的显性克隆。这里要探讨的中心假设是高风险 NB 其特点是广泛的瘤内和基质衍生的异质性，并含有预先存在的和 获得的亚克隆群体具有治疗抗性，可以通过合理选择来利用 针对性的代理。我们将在三个具体目标中检验我们的中心假设：1）定义频率和临床 亚克隆驱动突变的重要性； 2) 确定因抑制而造成的治疗脆弱性 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性 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，用于定义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物质 重点是证明抑制 FAK 会导致 ALK 具有强大的抗肿瘤活性 以及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 基于我们广泛的初步数据，将联合疗法转移到临床所需的理由 我们的癌基因驱动模型中的协同药物相互作用。我们认为这个项目意义重大，因为它将 产生新的基于机制的生物标志物定义的治疗策略，最终应该显着 改善高危 NB 患者的预后。这将解决未满足的主要需求，尽管这是前所未有的 在定义 NB 肿瘤发生的基本机制方面的发现，这些知识尚未转化为 显着改善高危疾病患者的预后。