Proj 1 - Targeting Evolving Therapy Resistance

项目 1 - 针对不断变化的治疗耐药性

基本信息

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
项目类别：
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

项目摘要

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，生存的孩子是留下长期副作用，其中许多可能会威胁生命。在这个更精确的疗法时代，为识别最佳目标而做出了巨大的努力。而分子的范式被靶向疗法具有巨大的希望，基因组研究表明，NB的特征是广泛肿瘤内遗传异质性，在标准期间经常选择亚克隆致癌驱动因素化学放疗。我们的小组发现碱受体酪氨酸激酶的功能收益突变为家族性NB的病因，同时与其他几个相同的突变共同发现作为最常见的体细胞单核苷酸变体，导致高达15％的有效致癌驱动器新诊断的高风险病例。我们最近的工作表明，在Alk-Ras-中激活突变 MAPK途径在复发NB基因组中高度富集，为深度和深处提供了动力这些途径内基因的亚克隆景观的全面表征治疗的连续性。这是该项目的动力，并提供了既适应的机会随着肿瘤的发展，治疗方法也会靶向锁骨突变，以防止获得耐化学疗法的主要克隆。这里要探索的中心假设是高风险NB 具有广泛的肿瘤内和基质衍生的异质性和港口现有的特征获得的亚克隆人群可以赋予可以合理选择的抗药性抗药性目标代理。我们将以三个特定目的测试中心假设：1）定义频率和临床亚克隆驱动器突变的重要性； 2）确定因抑制而赋予的治疗漏洞致癌碱和/或Ras-Mapk信号传导； 3）目标肿瘤细胞固有和外在致癌理性新颖治疗学发展的脆弱性。第一个目标将采用自定义的超深定义克隆和亚克隆体系结构以及诊断和突变景观的测序平台复发NB，包括PDX模型。 AIM 2致力于定义治疗性可利用的致癌性脆弱性的重点是证明抑制FAK会导致碱性抗肿瘤活性和通过这些途径抑制剂处理的RAS驱动的NB。最终目标将获得临床前将联合疗法转移到诊所所需的理由，以我们广泛的初步数据为基础在我们的癌基因驱动模型中的协同药物相互作用。我们认为这个项目很重要，因为它将导致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。这将满足尽管前所未有的主要未满足需求在定义NB肿瘤发生的基本机制时发现，这种知识尚未转化为高危疾病患者的预后大大改善。