Targeting Oncogenic ALK Signaling in Neuroblastoma

总结/摘要 神经母细胞瘤（NB）仍然是儿童癌症发病率和死亡率的主要原因。我们发现 ALK癌基因中的遗传性激活突变，并且这些相同的突变通常是体细胞性的， 在高风险NB肿瘤发生期间获得。我们的工作确立了ALK作为NB中易处理的分子靶点 并为ALK抑制治疗的临床开发提供了依据。第二次竞争性续约 建立在过去十年的六项重大发现基础上：1）我们发现大多数激活ALK突变 对第一代药物如克唑替尼不敏感; 2）我们证明化疗可以 使ALK突变NB对克唑替尼敏感，导致正在进行的III期试验; 3）我们确定劳拉替尼是唯一 ALK抑制剂对所有激活突变有效，并迅速启动了1期临床试验， 显示出显著的抗肿瘤活性，同时仍处于剂量递增中; 4）我们开发并实施了一种临床 将复发时肿瘤细胞中的基因组畸变与合理设计的 分子靶向药物（例如，用于ALK驱动的NB患者的ceritinib + ribociclib）已显示 协同活性; 5）我们表明劳拉替尼的上级活性是通过抑制 G2/M激酶; 6）我们发现ALK在绝大多数人的细胞表面大量表达， NB和其他儿科恶性肿瘤，并已制定免疫策略，因为ALK不是 在正常组织中表达。因此，这项新研究提案的长期目标是改善 通过利用上述势头，将NB儿童纳入合理的新组合和免疫系统， 治疗策略。这里的目标是确定调节适应性反应的机制， 使用劳拉替尼抑制ALK，并开发靶向血浆中ALK的治疗策略 膜的我们的中心假设是：i）ALK驱动的NB通过以下途径适应并存活于劳拉替尼治疗： 可以治疗靶向的机制;和ii）天然ALK的免疫靶向是生物学的， 与大多数NB患者和其他儿童肿瘤的可识别子集相关。我们将测试 我们的中心假设有两个具体目标：1）阐明ALK激酶适应性耐药的机制 与劳拉替尼抑制，以确定最佳组合策略，将导致改善和持续 2）开发高度特异性的基于抗体的方法，靶向NB上的细胞表面ALK 和其他表达ALK的儿科癌症。我们认为这一建议意义重大，因为它将导致一个新的 基于机制的治疗策略，将解决主要未满足的需求，尽管前所未有的 尽管在定义NB肿瘤发生的基本机制方面有一些发现，但这些知识尚未转化为 显著改善的结果。

SUMMARY/ABSTRACT Neuroblastoma (NB) remains a leading cause of childhood cancer morbidity and mortality. We discovered heritable activating mutations in the ALK oncogene, and that these same mutations are frequently somatically acquired during high-risk NB tumorigenesis . Our work established ALK as a tractable molecular target in NB and provided the rationale for the clinical development of ALK inhibition therapy. This second competitive renewal builds on six major discoveries over the last decade: 1) we showed that the majority of activating ALK mutations are not sensitive to first generation drugs such as crizotinib; 2) we demonstrated that chemotherapy could sensitize ALK mutant NBs to crizotinib, leading to an ongoing Phase 3 trial; 3) we identified lorlatinib as the only ALK inhibitor that is effective against all activating mutations and rapidly opened a phase 1 clinical trial that is showing significant anti-tumor activity while still in dose escalation; 4) we developed and implemented a clinical trial matching genomic aberrations in tumor cells at the time of relapse to rationally designed combinations of molecularly targeted agents (e.g. ceritinib + ribociclib for patients with ALK-driven NB) that have shown synergistic activity in our lab; 5) we showed that the superior activity of lorlatinib is mediated through inhibition of G2/M kinases; and 6) we showed that ALK is abundantly expressed on the cell surface of the vast majority of NBs and other pediatric malignancies, and have developed immunotherapeutic strategies since ALK is not expressed on normal tissues. Thus, the long-term goal of this new research proposal is to improve outcomes for children with NB by leveraging the momentum above into rational new combinatorial and immunotherapeutic treatment strategies. The objective here is to identify mechanisms regulating adaptive responses to targeted ALK inhibition with lorlatinib and to develop therapeutic strategies aimed at targeting ALK in the plasma membrane. Our central hypotheses are that i) ALK-driven NBs adapt to and survive therapy with lorlatinib via mechanisms that can be therapeutically targeted; and ii) immunotherapeutic targeting of native ALK is of biologic relevance to the majority of patients with NB and to identifiable subsets of other childhood tumors. We will test our central hypothesis in two specific aims: 1) Elucidate mechanisms of adaptive resistance to ALK-kinase inhibition with lorlatinib to identify optimal combination strategies that will result in improved and sustained therapeutic efficacy; 2) Develop highly specific antibody-based approaches to target cell surface ALK on NBs and other ALK-expressing pediatric cancers. We consider this proposal significant because it will result in a new mechanism-based therapeutic strategy that will address the major unmet need that, despite unprecedented discoveries in defining the basic mechanisms of NB tumorigenesis, this knowledge has not yet translated into significantly improved outcomes.