Uncovering Therapeutic Targets in Pediatric High Grade Gliomas with the H3K27M Mutation

项目摘要 在儿童中，影响大脑的肿瘤导致的癌症相关死亡比任何其他类型的肿瘤都要多。它是 因此，这对确定新的治疗方法至关重要。在儿科患者中，最具破坏性的脑瘤类型之一 弥漫性桥脑胶质瘤(DIPG)。我们最近对这种致命疾病的理解是 由重要发现推动，包括发现大多数DIPG肿瘤含有组蛋白 H3K27M突变。这种突变导致H3K27残基的全局低甲基化，是病理性的 这是这种疾病的标志。 申请人已经发现Wnt5a和STAT3信号对增殖和 H3K27M肿瘤存活和抑制这些途径可恢复H3K27甲基化模式的减少 并导致肿瘤细胞死亡。该项目旨在进一步了解STAT3对H3K27M的关键作用 并验证STAT3作为治疗DIPG肿瘤的药物靶点。另一个目标是开发更多的儿科 患者来自高级别胶质瘤异种移植瘤和细胞系。这些技术将可推广到其他 恶性脑肿瘤发生的分子驱动因素。这项拟议的研究意义重大，因为它 预计将垂直推进治疗DIPG肿瘤的选择。 应聘者是一名医学博士/博士学位的神经外科医生兼科学家，在儿科脑部接受过高级临床培训。 其职业目标是通过基础和基础治疗来推进恶性脑肿瘤的治疗策略 翻译研究。职业发展计划和研究将由Jann Sarkaria博士指导，她是一名 研究目标与候选人一致的内科科学家。这项提议结合了 候选人、导师和研究机构的长处，以便为 成为一名成功的独立神经外科医生兼科学家的候选人。

Project Summary In children, tumors affecting the brain result in more cancer-related deaths than any other type of tumor. It is thus critical to identify new therapies. Among pediatric patients, one of the most devastating brain tumor types is Diffuse Intrinsic Pontine Gliomas (DIPG). Our understanding of this deadly disease has recently been advanced by important discoveries, including the finding that the majority of DIPG tumors harbor the histone H3K27M mutation. This mutation results in global hypomethylation of H3K27 residues and is the pathological hallmark for this disease. The applicant has discovered that Wnt5a and STAT3 signaling are critically important for proliferation and survival of H3K27M tumors and inhibiting these pathways restores the reduced H3K27 methylation patterns and leads to tumor cell death. This project aims to further understand how STAT3 is critical for H3K27M tumors and validate STAT3 as a drug target in DIPG tumors. A further goal is to develop additional pediatric patient derived high grade glioma xenografts and cell lines. These techniques will be generalizable to other molecular drivers of tumorigenesis in malignant brain tumors. The proposed research is significant because it is expected to vertically advance therapeutic options for treating DIPG tumors. The candidate is an MD/PhD trained neurosurgeon-scientist with advanced clinical training in pediatric brain tumors whose career goal is to advance treatment strategies for malignant brain tumors through basic and translational research. The career development plan and research will be mentored by Dr. Jann Sarkaria, a physician-scientist whose research goals are in alignment with the candidate. This proposal combines the strengths of the candidate, the mentors, and the research institution in order to provide an opportunity for the candidate to become a successful independent neurosurgeon-scientist.