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/文摘

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