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 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标并为 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

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）

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma.

克唑替尼在神经母细胞瘤临床前模型中与化疗具有协同作用。

DOI：
发表时间：
2016-02-15
期刊：
影响因子：
0
作者：
Krytska, Kateryna;Ryles, Hannah T;Sano, Renata;Raman, Pichai;Infarinato, Nicole R;Hansel, Theodore D;Makena, Monish R;Song, Michael M;Reynolds, C Patrick;Mossé, Yael P
通讯作者：
Mossé, Yael P

Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.

克唑替尼治疗难治性实体瘤或间变性大细胞淋巴瘤儿科患者的安全性和活性：儿童肿瘤学组 1 期联合研究。

DOI：
10.1016/s1470-2045(13)70095-0
发表时间：
2013-05
期刊：
The Lancet. Oncology
影响因子：
0
作者：
Mossé YP;Lim MS;Voss SD;Wilner K;Ruffner K;Laliberte J;Rolland D;Balis FM;Maris JM;Weigel BJ;Ingle AM;Ahern C;Adamson PC;Blaney SM
通讯作者：
Blaney SM

Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma.

全基因组连锁分析，以确定家族性神经母细胞瘤中 ALK 突变外显率的遗传修饰因子。

DOI：
发表时间：
2011
期刊：
影响因子：
1.8
作者：
Devoto, Marcella;Specchia, Claudia;Laudenslager, Marci;Longo, Luca;Hakonarson, Hakon;Maris, John;Mossé, Yael
通讯作者：
Mossé, Yael

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：
发表时间：
2021
期刊：
影响因子：
4.6
作者：
Samoyedny, Andrew;Srinivasan, Abhay;States, Lisa;Mosse, Yael P;Alai, Emma;Pawel, Bruce;Pogoriler, Jennifer;Shellikeri, Sphoorti;Vatsky, Seth;Acord, Michael;Escobar, Fernando;Edgar, J Christopher;Maris, John M;Cahill, Anne Marie
通讯作者：
Cahill, Anne Marie

Anaplastic Lymphoma Kinase as a Cancer Target in Pediatric Malignancies.

间变性淋巴瘤激酶作为儿科恶性肿瘤的癌症靶点。