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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/文摘