Targeting Oncogenic ALK Signaling in Neuroblastoma

靶向神经母细胞瘤中的致癌 ALK 信号转导

基本信息

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
项目类别：
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

项目摘要

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。我们发现了碱性癌基因中可遗传的激活突变，并且这些相同的突变经常是体面的在高危NB肿瘤发生期间获得。我们的工作将ALK确立为NB中的可寓言分子靶标并为ALK抑制疗法的临床发展提供了理由。第二次竞争更新在过去十年中建立在六个主要发现的基础上：1）我们表明大多数激活ALK突变对第一代药物（例如克唑替尼）不敏感； 2）我们证明化学疗法可以将Alk突变体NBS敏感到Crizotinib，导致3阶段试验； 3）我们确定洛拉替尼是唯一的 ALK抑制剂有效地抵抗所有激活突变，并迅速开放了一项1期临床试验在仍处于剂量升级的同时，显示出明显的抗肿瘤活性； 4）我们开发并实施了临床在复发到合理设计的组合时，试验肿瘤细胞中基因组畸变的试验已显示的分子靶向剂（例如，碱性NB患者的ceritinib + ribociclib）已显示我们实验室的协同活动； 5）我们表明劳拉替尼的优质活性是通过抑制作用介导的 G2/m激酶； 6）我们表明，Alk在绝大多数的细胞表面上大量表达 NBS和其他儿科恶性肿瘤，并且已经制定了免疫治疗策略，因为Alk不是在正常组织上表达。因此，这项新研究建议的长期目标是改善结果通过利用上面的动量为理性的新组合和免疫治疗方法，患有NB的孩子治疗策略。这里的目的是确定调节针对目标自适应反应的机制用劳拉替尼抑制ALK，并制定旨在靶向血浆中碱的治疗策略膜。我们的核心假设是，i）ALK驱动的NBS适应并通过Lorlatinib通过可以针对治疗的机制； ii）天然ALK的免疫治疗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有关。我们将测试我们在两个具体目的中的中心假设：1）阐明对碱性激酶的适应性抗性机制用洛拉替尼抑制以确定最佳组合策略，从而改善和持续治疗功效； 2）开发基于高度特异的基于抗体的方法来靶细胞表面碱在NBS上和其他表达ALK的儿科癌症。我们认为这一建议很重要，因为它将导致新的基于机制的治疗策略，该策略将解决主要未满足的需求，尽管前所未有在定义NB肿瘤发生的基本机制时发现，这种知识尚未转化为大大改善了结果。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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
影响因子：
0
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

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
影响因子：
0
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

Targeting ALK in neuroblastoma--preclinical and clinical advancements.