Targeting Pediatric Cancer Vulnerabilities

针对儿童癌症的脆弱性

• 批准号: 10737704
• 负责人: Kimberly Stegmaier
• 金额: $ 106.62万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2030-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737704
• 关键词: Acute Myelocytic Leukemia; Adult; Area; Biology; CRISPR screen; Cancer Model; Caring; Cessation of life; Chemicals; Child; Childhood; Childhood Solid Neoplasm; Cytotoxic Chemotherapy; Dedications; Dependence; Disease; Disincentive; Drug Targeting; Ensure; Epigenetic Process; Ewings sarcoma; Fusion Oncogene Proteins; Genomic approach; Goals; Immune checkpoint inhibitor; Immunologist; Immunotherapy; Laboratories; Lead; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Marketing; Medicine; Molecular; Morbidity - disease rate; Mutation; Oncogenic; Operative Surgical Procedures; Pediatric Oncologist; Pediatric Oncology; Pediatrics; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Proteins; Radiation; Research Personnel; Risk; Role; School-Age Population; Scientist; Structural Biologist; Therapeutic; Time; Validation; Work; career; functional genomics; genome-wide; inhibitor; innovation; novel; novel therapeutics; programs; protein degradation; response; sarcoma; success; therapeutic target; therapy development; transcription factor; tumor

Project Summary / Abstract Despite progress in understanding the molecular basis of childhood malignancies, cancer remains the leading cause of disease-related death in school age children. Moreover, we are still treating these children with old approaches, including cytotoxic chemotherapy, radiation, and surgery, each with associated morbidities. Several roadblocks have hampered progress in treating children with cancer. First, cancer-promoting targets, such as transcription factor fusion oncoproteins, are quite common in pediatrics but make for challenging drug targets. Second, pediatric malignancies tend to have fewer mutations than adult cancers resulting in a decreased likelihood of response to immune checkpoint inhibitors. In sharp contrast, immune checkpoint inhibitors have transformed therapy for subsets of adult cancers. Third, there is a market disincentive for pharmaceutical companies to work on targets that are exclusive to pediatric cancers. Academic investigators must take the lead in de-risking these high priority pediatric targets through comprehensive target validation and identification of initial chemical leads. I am an investigator willing and equipped to take such a risk. I am a physician-scientist, pediatric oncologist innovator and have dedicated my career to the goal of precision pediatric oncology medicine. The time is right to tackle these vexing challenges in childhood cancer therapy development. I will focus predominantly on fusion-driven acute myeloid leukemias (AMLs) and the fusion- driven pediatric solid tumor Ewing sarcoma, two areas of deep expertise in my laboratory. The first objective of my future research program is to target oncogenic fusions in pediatric cancers. We will pioneer new strategies of targeted protein degradation to validate and mechanistically dissect their role in tumor maintenance and to develop inhibitors/degraders that will ultimately inform new therapies. I have led innovative chemical and functional genomic approaches to identify therapeutic targets for childhood cancer, such as the first Pediatric Cancer Dependency Map, genome-scale CRISPR-Cas9 screening in over 100 pediatric cancer models. Novel pediatric specific targets and innovative therapeutic concepts have emerged and will be the focus of our second objective. We aim to deeply understand these targets mechanistically and to identify chemical perturbagens of the top priority dependencies by deploying innovative chemical biology strategies. My third objective leverages my expertise in functional genomics and epigenetics to identify and drug the regulators of key targets of immunotherapies in childhood cancer. My success in these bold endeavors will be ensured by a collaborative team of world-class chemists, structural biologists, immunologists, and epigenetics experts. The discovery of drugs that target pediatric oncogenic fusions and other novel Achilles heels, and the converting of unresponsive childhood malignancies to immunotherapy responsive, would truly be paradigm shifting for children suffering from these diseases.

项目摘要 /摘要 尽管在了解儿童恶性肿瘤的分子基础方面取得了进展，但癌症仍然是领先的 学龄儿童与疾病有关的原因。而且，我们仍在用老的孩子对待这些孩子 方法，包括细胞毒性化学疗法，放射线和手术，每种都有相关的病因。 几个障碍在治疗癌症儿童方面已阻碍了进步。首先，促进癌症的目标， 例如转录因子融合癌蛋白，在儿科中很常见，但使得具有挑战性的药物 目标。其次，小儿恶性肿瘤的突变往往比成人癌的突变少，导致 对免疫检查点抑制剂反应的可能性降低。形成鲜明对比的是免疫检查点 抑制剂已转化了成人癌症亚群的治疗。第三，有一个市场不利的市场 制药公司致力于针对儿科癌症独有的靶标。学术研究人员 必须通过全面的目标验证来降低这些高优先儿科目标的危险 并鉴定初始化学铅。我是一名愿意并有能力冒险的调查员。 我是医师科学家，儿科肿瘤学家创新者，并致力于精确的目标 小儿肿瘤医学。在儿童期癌症治疗中应对这些烦恼的挑战的时候是正确的 发展。我将主要关注融合驱动的急性髓样白血病（AML）和融合 - 驱动的小儿实体肿瘤肉瘤，我的实验室中有两个深厚的专业知识领域。第一个目标 我未来的研究计划是针对儿科癌症中的致癌融合。我们将开拓新策略 靶向蛋白质降解以验证和机械机械地剖析其在肿瘤维持中的作用和 开发抑制剂/降解器，最终将为新疗法提供信息。我领导了创新的化学化学和 鉴定儿童癌症治疗靶点的功能基因组方法，例如第一个小儿 癌症依赖图，基因组规模CRISPR-CAS9在100多个小儿癌模型中筛查。小说 小儿特定的靶标和创新的治疗概念已经出现，将成为我们的重点 第二个目标。我们旨在深入理解这些目标并识别化学物质 通过部署创新的化学生物学策略，首要优先级依赖性的急性脉动。我的第三个 客观利用我在功能基因组学和表观遗传学方面的专业知识来识别和吸毒 儿童癌症免疫疗法的主要靶标。我在这些大胆努力中的成功将由 世界一流化学家，结构生物学家，免疫学家和表观遗传学专家的合作团队。这 发现针对小儿致癌融合和其他新颖的致命弱点的药物，以及转换 对免疫疗法的反应反应的童年无反应，这确实是范式转移的 患有这些疾病的孩子。