Infant and Toddler Brain Tumors

描述（由申请人提供）：尽管进行了积极的手术治疗，联合化疗和干细胞抢救，在某些情况下还进行了放疗，但患有恶性脑肿瘤的幼儿的5年无事件生存率为15-30%。对这些儿童进行更有效和毒性更低的治疗的一个关键障碍是缺乏对这些年龄特异性肿瘤生存至关重要的分子途径的功能知识。此外，婴幼儿脑肿瘤的发病率很低，是孤儿病，没有引起明显的行业兴趣。在这项提案中，我们汇集了一些世界领先的高通量RNAi分析专家，以创新的新方法来确定候选治疗靶点，以测试和优先考虑潜在的协同联合疗法，并汇集了一个经验丰富的脑肿瘤转化研究团队，以解决高侵略性治疗未能改善婴幼儿脑肿瘤预后的具体临床问题。我们广泛的、长期的目标是使婴幼儿脑癌的治愈率翻一番。我们的具体目的是：1)评估cdk4 /6抑制在ATRT和成神经管细胞瘤的临床相关小鼠模型中的疗效；2)寻找婴幼儿脑肿瘤新的治疗靶点；3)将一种高效的药物组合推进到婴幼儿脑肿瘤的人体临床试验阶段。预期的结果是一种联合治疗方案，在已建立的、体积庞大的、临床相关的婴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高毒性和无效的治疗方案，转而采用具有更高疗效和更低毒性的靶向方法。

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.