The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma

项目总结/摘要 神经母细胞瘤（一种发育中的交感神经系统肿瘤）中复发性体细胞突变的相对缺乏 神经系统，挑战了为这个毁灭性的童年设计有效的靶向治疗的努力 癌这种令人失望的情况的一个例外是突变的ALK受体酪氨酸激酶， 它在神经母细胞瘤中出现的频率相对较高，并已被强调为重要的 在这种肿瘤的发病机制中起作用，也是药物开发的关键目标。研究进展 过去5年在主要研究者（PI）实验室工作（1 R 01 CA 148688），最近获得 初步数据表明，将改进的ALK抑制剂（ALKi）与新的 需要协同抑制化合物来诱导神经母细胞瘤患者的持久缓解， 激活ALK突变。这一预计的进展将需要与更多的起源知识相结合 对这种治疗的耐药性，以及将ALK导向治疗扩展到更多患者的策略， 患者为了应对这些挑战，PI将探讨三个关键问题， 将神经母细胞瘤的靶向治疗研究带入下一个时代--这一研究的长期目标。目标1： ALKi的细胞毒性是否可以通过将这些药物与以下药物组合来改善和延迟耐药性？ 转录CDK抑制剂（CDKi）？假设-CDKi与ALKi在ALK突变， MYCN非扩增神经母细胞瘤细胞通过破坏转录调控产生协同活性 通过增强对ALK信号传导的抑制。目的2：ALK突变， MYCN扩增的神经母细胞瘤细胞对ALK抑制剂产生耐药性？假设-收购 对ALKi的抗性与超级增强子向BRD 4增强子位点的全局重新分布有关， 到可以利用来获得治疗效果的新型分子弱点。目的3：野生型ALK 裂解可以作为高危神经母细胞瘤的治疗靶点吗？假设-蛋白水解裂解 ALK的胞外结构域的治疗靶点可以通过MMP 9抑制来阻止NB细胞 迁移这项更新提案的积极结果显然将使高危神经母细胞瘤儿童受益 也可能使表达异常ALK的不同癌症患者受益， 间变性大细胞淋巴瘤

PROJECT SUMMARY/ABSTRACT The relative scarcity of recurrent somatic mutations in neuroblastoma, a tumor of the developing sympathetic nervous system, has challenged efforts to devise effective targeted therapies for this devastating childhood cancer. One exception to this otherwise disappointing picture is the mutated ALK receptor tyrosine kinase, which appears at a relatively high frequency in neuroblastoma, and has been highlighted as an important player in the pathogenesis of this tumor and a key target for drug development. Research progress over the past 5 years in the principal investigator’s (PI’s) laboratory (under 1R01CA148688) and recently acquired preliminary data indicate that targeted therapies combining improved ALK inhibitors (ALKi) with novel synergistic inhibitory compounds are needed to induce durable remissions in neuroblastoma patients with activating ALK mutations. This projected advance will need to be coupled with greater knowledge of the origins of resistance to such treatment, as well as strategies to extend ALK-directed therapy to larger numbers of patients. To address these challenges, the PI will pursue three pivotal questions that are intended to propel targeted therapy research in neuroblastoma into the next era – the long-term goal of this research. Aim 1: Can the cytotoxicity of ALKi be improved and resistance delayed by combining these agents with transcriptional CDK inhibitors (CDKi)? Hypothesis – The combination of CDKi with ALKi in ALK-mutated, MYCN nonamplified neuroblastoma cells produces synergistic activity by disrupting transcriptional regulation through enhanced inhibition of ALK signaling. Aim 2: What are the mechanisms by which ALK-mutated, MYCN-amplified neuroblastoma cells develop resistance to ALK inhibitors? Hypothesis – The acquisition of resistance to ALKi is associated with global redistribution of super-enhancers to BRD4 enhancer sites, leading to novel molecular vulnerabilities that could be exploited for therapeutic gain. Aim 3: Can wild-type ALK cleavage be leveraged as a therapeutic target in high-risk neuroblastoma? Hypothesis – Proteolytic cleavage of the extracellular domain of ALK could be therapeutically targeted through MMP9 inhibition to impede NB cell migration. Positive results in this renewal proposal would clearly benefit children with high-risk neuroblastoma and may also benefit patients with different cancers that express aberrant ALK, from non-small cell lung cancer to anaplastic large-cell lymphoma.