Targeting Oncogenic ALK Signaling in Neuroblastoma

靶向神经母细胞瘤中的致癌 ALK 信号转导

• 批准号: 10626812
• 负责人: Yael P Mosse
• 金额: $ 41.8万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626812
• 关键词: Address; Antibodies; Antibody-drug conjugates; Automobile Driving; Biological; Cell Maintenance; Cell membrane; Cell surface; Child; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Dose; Drug resistance; ERBB2 gene; Epidermal Growth Factor Receptor; Epigenetic Process; Generations; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health; Heritability; Histologic; Human; Immune Targeting; Immunotherapeutic agent; In Vitro; Knowledge; Laboratories; Lead; Ligands; Malignant Childhood Neoplasm; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator; Mission; Molecular; Molecular Target; Morbidity - disease rate; Mutate; Mutation; Neuroblastoma; Newly Diagnosed; Normal tissue morphology; Nucleotides; Oncogenes; Oncogenic; Outcome; PLK1 gene; PTPN11 gene; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Play; Positioning Attribute; Protein Tyrosine Kinase; Protein-Kinase Oncogenes; Proteomics; Public Health; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Relapse; Research; Research Proposals; Resistance; Role; Selection for Treatments; Signal Transduction; Surface; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Tyrosine-Kinase Oncogenes; United States National Institutes of Health; Work; anaplastic lymphoma kinase; chemotherapy; chimeric antibody; clinical biomarkers; clinical development; clinically relevant; combinatorial; crizotinib; cytotoxicity; dimer; evidence base; gain of function mutation; genomic aberrations; high risk; improved; improved outcome; inhibitor; innovation; mortality; mutant; neoplastic cell; neuroblastoma cell; novel; novel therapeutic intervention; patient derived xenograft model; phase III trial; pre-clinical; prevent; pyrrolobenzodiazepine; rational design; receptor density; resistance mechanism; response; targeted agent; targeted treatment; therapeutic target; therapeutically effective; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor heterogeneity; tumorigenesis

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.

摘要/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 癌基因中的可遗传激活突变，并且这些相同的突变经常发生在体细胞上 在高风险 NB 肿瘤发生过程中获得。我们的工作将 ALK 确立为 NB 中易于处理的分子靶点 并为 ALK 抑制疗法的临床开发提供依据。这是第二次竞争性更新 建立在过去十年的六项重大发现的基础上：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，从而启动正在进行的 3 期试验； 3) 我们确定劳拉替尼是唯一的 ALK 抑制剂对所有激活突变均有效，并迅速启动了 1 期临床试验 在剂量递增的同时显示出显着的抗肿瘤活性； 4）我们开发并实施了临床 试验将复发时肿瘤细胞的基因组畸变与合理设计的组合相匹配 分子靶向药物（例如用于 ALK 驱动的 NB 患者的色瑞替尼 + ribociclib） 我们实验室的协同活动； 5) 我们证明了lorlatinib的卓越活性是通过抑制介导的 G2/M 激酶； 6) 我们发现 ALK 在绝大多数细胞表面大量表达 NB 和其他儿科恶性肿瘤，并已开发出免疫治疗策略，因为 ALK 不 在正常组织上表达。因此，这项新研究提案的长期目标是改善结果 利用上述势头进行合理的新组合和免疫治疗 治疗策略。这里的目标是确定调节针对目标的适应性反应的机制 使用lorlatinib 抑制 ALK 并制定针对血浆中 ALK 的治疗策略 膜。我们的中心假设是 i) ALK 驱动的 NB 通过 lorlatinib 适应并存活下来 可作为治疗目标的机制； ii) 天然 ALK 的免疫治疗靶向具有生物活性 与大多数 NB 患者以及其他儿童肿瘤的可识别亚群相关。我们将测试 我们的中心假设有两个具体目标：1) 阐明 ALK 激酶适应性耐药机制 劳拉替尼抑制以确定最佳组合策略，从而改善和持续 治疗效果； 2) 开发基于抗体的高度特异性方法来靶向 NB 上的细胞表面 ALK 和其他表达 ALK 的儿童癌症。我们认为该提案意义重大，因为它将产生新的 基于机制的治疗策略将解决主要的未满足需求，尽管这是前所未有的 在定义 NB 肿瘤发生的基本机制方面的发现，这些知识尚未转化为 显着改善结果。

项目成果

Image-Guided Biopsy for Relapsed Neuroblastoma: Focus on Safety, Adequacy for Genetic Sequencing, and Correlation of Tumor Cell Percent With Quantitative Lesion MIBG Uptake.

复发性神经母细胞瘤的图像引导活检：关注安全性、基因测序的充分性以及肿瘤细胞百分比与定量病变 MIBG 摄取的相关性。

• DOI: 10.1200/po.20.00171
• 发表时间: 2021
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Samoyedny,Andrew;Srinivasan,Abhay;States,Lisa;Mosse,YaelP;Alai,Emma;Pawel,Bruce;Pogoriler,Jennifer;Shellikeri,Sphoorti;Vatsky,Seth;Acord,Michael;Escobar,Fernando;Edgar,JChristopher;Maris,JohnM;Cahill,AnneMarie
• 通讯作者: Cahill,AnneMarie

An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma.

• DOI: 10.1126/scitranslmed.aau9732
• 发表时间: 2019-03-13
• 期刊: Science translational medicine
• 影响因子: 17.1

Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma.

• DOI: 10.1158/1078-0432.ccr-16-1114
• 发表时间: 2017-06-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Wood AC;Krytska K;Ryles HT;Infarinato NR;Sano R;Hansel TD;Hart LS;King FJ;Smith TR;Ainscow E;Grandinetti KB;Tuntland T;Kim S;Caponigro G;He YQ;Krupa S;Li N;Harris JL;Mossé YP
• 通讯作者: Mossé YP

Targeting ALK in neuroblastoma--preclinical and clinical advancements.

• DOI: 10.1038/nrclinonc.2012.72
• 发表时间: 2012-05-15
• 期刊: Nature reviews. Clinical oncology

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).

• DOI: 10.1158/1078-0432.ccr-20-4224
• 发表时间: 2021-07-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Foster JH;Voss SD;Hall DC;Minard CG;Balis FM;Wilner K;Berg SL;Fox E;Adamson PC;Blaney SM;Weigel BJ;Mossé YP
• 通讯作者: Mossé YP