Infant and Toddler Brain Tumors

描述(申请人提供)：尽管积极的手术治疗，联合化疗和干细胞挽救，在某些情况下放射治疗，患有恶性脑瘤的儿童有15%-30%的5年无事件存活率。对于这些儿童来说，更有效和毒性较低的治疗方法的一个关键障碍是缺乏对这些年龄特定的肿瘤生存至关重要的分子通路的功能知识。此外，婴儿和蹒跚学步的儿童脑瘤的发病率很低，以至于它们是孤儿疾病，没有引起明显的行业兴趣。在这项建议中，我们汇集了一些世界领先的高通量RNAi分析专家，以确定候选治疗靶点，以创新的新方法测试并优先考虑潜在的协同联合治疗，以及一个经验丰富的脑瘤转化研究团队，以解决高侵入性治疗未能改善患有脑瘤的婴幼儿的特定临床问题。我们广泛而长期的目标是将患有脑癌的婴幼儿的治愈率提高一倍。我们的具体目标是1)评估CDK 4/6抑制在临床相关的ATRT和髓母细胞瘤小鼠模型中的疗效；2)寻找婴幼儿脑瘤的新治疗靶点；3)将一种高效的药物组合推进到针对婴幼儿脑瘤的人类临床试验的点。预期的结果是一种联合治疗方案，在已建立的、庞大的、临床相关的婴儿和幼儿脑癌小鼠模型中产生持久的缓解。这项工作的意义在于，儿科神经肿瘤学家将放弃我们目前使用的剧毒和无效的治疗方案，转而采用具有更高疗效和更低毒性的靶向治疗方案。

DESCRIPTION (provided by applicant): Despite aggressive treatment with surgery, combination chemotherapy with stem cell rescue, and in some cases radiation, young children with malignant brain tumors have a 5-year event-free survival rate of 15-30%. A critical barrier to more effective and less toxic therapies for these children is the paucity of functional knowledge about the molecular pathways that are critical for survival of these age-specific tumors. Furthermore, the incidence of infant and toddler brain tumors is low enough that they are orphan diseases, which attract no appreciable industry interest. In this proposal, we bring together some of the world's leading experts on high throughput RNAi assays to identify candidate therapeutic targets with an innovative new approach to test and prioritize potentially synergistic combination therapies and a highly experienced brain tumor translational research team to solve the specific clinical problem that highly aggressive therapies are failing to improve outcomes in infants and toddlers with brain tumors. Our broad, long-term goal is to double the cure rate for infants and toddlers with brain cancer. Our specific aims are 1) To assess the efficacy of Cdk 4/6 inhibition in clinically relevant mouse models of ATRT and medulloblastoma; 2) To identify novel therapeutic targets in infant and toddler brain tumors; 3) To advance one highly effective drug combination to the point of human clinical trials for infants and toddlers with brain tumors. The expected outcome is a combination therapy regimen that produces durable remission in established, bulky, clinically relevant mouse models of infant and toddler brain cancer. The significance of this work is that pediatric neuro-oncologists will abandon the highly toxic and ineffective therapeutic regimens that we are currently using in favor of a targeted approach that has higher efficacy and less toxicity.