Developing new therapeutic strategies for pediatric tumors that lack clinically actionable mutations

为缺乏临床可行突变的儿科肿瘤开发新的治疗策略

基本信息

批准号：
10672878
负责人：
Paul Geeleher
金额：
$ 46.96万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672878
关键词：
Address Adult Affect Antineoplastic Agents Biological Assay Biology Bone neoplasms CRISPR screen Cancer Patient Cancer cell line Cause of Death Cell Line Cells Chemotherapy and/or radiation Child Childhood Childhood Cancer Treatment Childhood Solid Neoplasm Clinic Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Communities Computing Methodologies Cytotoxic Chemotherapy Data Data Set Dependence Dimensions Disease Drug Combinations Drug Screening Drug Synergism Drug Targeting Drug resistance Encyclopedias Ewings sarcoma Future Gene Expression Genes Genome Genomics Goals Heterogeneity Immunotherapy In Vitro Knock-out Machine Learning Malignant Childhood Neoplasm Malignant Neoplasms Maps Methodology Methods Methylation Mutation Nature Neuroblastoma Patient Care Patients Pediatric Neoplasm Pharmaceutical Preparations Poly(ADP-ribose) Polymerase Inhibitor Relapse Research Research Personnel Resistance Resource Sharing Saint Jude Children&apos s Research Hospital Somatic Mutation Technology Testing Therapeutic Tumor Subtype Work actionable mutation cancer genome cancer immunotherapy cancer subtypes cancer therapy chemotherapy clinical translation clinically actionable disorder subtype genome sequencing high risk high throughput screening improved in vivo mouse model neoantigens neuroblastoma cell novel novel drug combination novel therapeutic intervention novel therapeutics patient derived xenograft model pre-clinical precision medicine preclinical study programs rapid growth resistance mechanism resistance mutation response screening standard of care synergism targeted cancer therapy tool transcriptomics tumor tumor heterogeneity whole genome

项目摘要

PROJECT SUMMARY / ABSTRACT Cancer is the leading disease-related cause of death in children. Treatment has remained largely unchanged in decades, relying primarily on aggressive cytotoxic chemotherapy and radiation—these therapies have debilitating long-term consequences. Precision medicine has yet to make a major impact on childhood cancer because, while thousands of pediatric tumor genomes have been sequenced, most children have very few somatic mutations compared to adult cancers. This means targeted cancer drugs are not an option for most children and fewer tumor-specific neoantigens means most immunotherapies are ineffective. However, in the last 5 years, large-scale CRISPR and drug screening studies in cancer cell lines, such as the Dependency Map (DepMap), have shown that in many cancers, unmutated genes can also act as potent drug targets. These genes are known as non-oncogene dependencies. The overall goal of this project is to overcome the low mutation burden, by identifying the druggable non-oncogene dependencies of pediatric tumors and to perform the requisite in vitro and in vivo experimental work to move these therapies to the clinic. We will identify these non-oncogene dependencies by applying tools from machine learning to perform integrative analysis of large pre-clinical screening datasets (such as DepMap, CCLE, and PRISM) with patient tumor -omics data. This will allow us to nominate specific non-oncogene dependencies for pediatric tumor subtypes, defined based on, for example, whole-genome gene expression or methylation data. We will mechanistically validate the top hits using in vitro experimental assays. Additionally, almost all curative cancer treatments involve the rational combination of multiple therapies, however, existing methods to predict effective combinations perform poorly when tested on unseen data. Thus, our second aim is to apply an approach that we have developed based on targeted CRISPR knockout screening to identify synergistic drug combinations. We will validate these combinations in vivo using mouse models with patient-derived xenografts, leveraging shared resources already established at St. Jude. Finally, tumor heterogeneity is ultimately the downfall of every known cancer treatment; however, in pediatric tumors where the mutation burden is low, much of this heterogeneity is driven by cell state, rather than specific somatic mutations. We will dissect the influence of cell state on drug resistance using single-cell and spatial transcriptomics technologies applied to a drug-treated spontaneous mouse model of neuroblastoma. This will ultimately allow us to nominate new drug combinations explicitly targeting drug-resistant cell states. Overall, this research program will aim to build a pipeline at St. Jude to overcome some of the main challenges posed by the low number of somatic mutations in pediatric tumors and identify new therapeutic strategies for these patients. We have assembled a diverse world-class team of researchers with all components necessary for an eventual impact on patient care.

项目摘要 /摘要癌症是儿童与疾病有关的主要死亡原因。治疗仍然很大不变几十年来，主要依靠侵袭性的细胞毒性化疗和放射线 - 这些疗法具有长期后果使人衰弱。精密医学尚未对儿童癌症产生重大影响因为，尽管已经对成千上万的小儿肿瘤基因组进行了测序，但大多数儿童的少数很少与成人癌症相比，体细胞突变。这意味着针对性的癌症药物不是大多数人的选择儿童和较少的肿瘤特异性新抗原意味着大多数免疫疗法无效。但是，在过去的5年中，大规模的CRISPR和癌细胞系中的药物筛查研究，例如依赖性图（DEPMAP）表明，在许多癌症中，未分泌的基因也可以充当潜在的药物目标。这些基因被称为非癌基因依赖性。该项目的总体目标是克服低突变伯嫩，通过识别可吸毒的儿科依赖性肿瘤并进行体外和体内实验性工作，以将这些疗法移至诊所。我们将通过应用机器学习中的工具来识别这些非血合物依赖性与患者的大型临床前筛选数据集（例如DepMap，Ccle和Prism）的综合分析肿瘤数据。这将使我们能够提名小儿肿瘤的特定非癌基因依赖性亚型，基于例如全基因组基因表达或甲基化数据定义。我们将使用体外实验测定法对最高命中进行机械验证。此外，几乎所有治愈性癌症疗法都涉及多种疗法的合理组合，但是，在对看不见的数据进行测试时，现有的预测有效组合的方法效果较差。那，我们的第二个目的是采用我们基于目标CRISPR淘汰的方法筛选以鉴定协同的药物组合。我们将使用鼠标在体内验证这些组合具有患者衍生异种移植物的模型，利用圣裘德已经建立的共享资源。最后，肿瘤异质性最终是每种已知癌症治疗的垮台。但是，在儿科突变燃烧较低的肿瘤，这种异质性的大部分是由细胞状态驱动的，而不是特定的体细胞突变。我们将使用单细胞和空间剖析细胞态对耐药性的影响转录组技术应用于神经母细胞瘤的药物治疗的赞助小鼠模型。这会最终使我们能够提名新的药物组合明确靶向耐药细胞态。总体而言，该研究计划将旨在在圣裘德建立一条管道，以克服一些主要挑战由小儿肿瘤中的体细胞突变数量少，并确定新的治疗策略这些患者。我们已经组建了一个潜水世界一流的研究人员团队，并拥有所有必要的组件为了对患者护理产生影响。