Targeting Pediatric Cancer Vulnerabilities

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，但癌症仍然是主要的 学龄儿童疾病相关死亡原因。此外，我们仍在为这些儿童提供老年治疗 方法，包括细胞毒性化疗、放射和手术，每种方法都有相关的发病率。 几个障碍阻碍了治疗癌症儿童的进展。第一，促进癌症的靶点， 例如转录因子融合癌蛋白，在儿科很常见，但对药物构成挑战 目标。其次，儿童恶性肿瘤往往比成人癌症突变更少，从而导致 降低了对免疫检查点抑制剂的反应可能性。与之形成鲜明对比的是免疫检查点 抑制剂已经改变了成人癌症亚类的治疗方法。第三，存在市场抑制因素 制药公司致力于儿科癌症的专属靶点。学术调查员 必须带头通过全面的目标验证来降低这些高优先级儿科目标的风险 以及识别初始化学物质的线索。我是一名调查员，愿意并有能力冒这样的风险。 我是一名内科科学家、儿科肿瘤学家创新者，并将我的职业生涯献给了精确的目标。 儿科肿瘤学。现在是解决儿童癌症治疗中这些令人烦恼的挑战的时候了 发展。我将主要集中在融合驱动的急性髓系白血病(AML)和融合- 驱动儿科实体瘤尤文肉瘤，两个领域的深厚专业知识在我的实验室。的第一个目标 我未来的研究计划是针对儿科癌症的致癌融合。我们将开创新的战略 以验证和机械地剖析它们在肿瘤维持中的作用以及 开发最终将成为新疗法的抑制剂/降解剂。我领导了创新的化学和 确定儿童癌症治疗靶点的功能基因组方法，例如第一个儿科 癌症依赖图，基因组规模的CRISPR-Cas9在100多个儿科癌症模型中的筛查。小说 儿科的具体目标和创新的治疗概念已经出现，并将成为我们 第二个目标。我们的目标是从机制上深入理解这些目标，并识别化学物质 通过部署创新的化学生物学战略，扰乱最优先的依赖关系。我的第三个 目标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药物调节 儿童癌症免疫治疗的关键靶点。我在这些大胆的努力中的成功将由一个 由世界级化学家、结构生物学家、免疫学家和表观遗传学专家组成的协作团队。这个 针对儿科致癌融合和其他新型跟腱的药物的发现，以及转化 儿童恶性肿瘤对免疫治疗反应迟钝，将真正转变为 患有这些疾病的儿童。

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.