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.

Public Health Relevance

This project is relevant to public health because the development of rational and effective ALK- inhibition strategies will impact patients with neuroblastoma as well as histologically diverse tumors where ALK is a critical mediator oncogenesis. Defining mechanisms of adaptive resistance to ALK inhibition will lead to more precise clinical biomarkers and therapies, as will exploitation of tumor-specific expression of ALK, a cell surface molecule that plays an essential role in tumor cell maintenance that will provide opportunities to develop a new class of immune targeting therapeutics. The research is highly relevant to the NIH mission and the urgent unmet need of developing rational evidence-based innovative treatment strategies to reduce the health burden of high-risk neuroblastoma, and perhaps other human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Mechanisms of Cancer Therapeutics - 1 Study Section (MCT1)
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Forry, Suzanne L
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Children's Hospital of Philadelphia
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Wood, Andrew C; Krytska, Kateryna; Ryles, Hannah T et al. (2017) Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma. Clin Cancer Res 23:2856-2868
Infarinato, Nicole R; Park, Jin H; Krytska, Kateryna et al. (2016) The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Cancer Discov 6:96-107
Krytska, Kateryna; Ryles, Hannah T; Sano, Renata et al. (2016) Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. Clin Cancer Res 22:948-60
Mossé, Yael P (2016) Anaplastic Lymphoma Kinase as a Cancer Target in Pediatric Malignancies. Clin Cancer Res 22:546-52
Bresler, Scott C; Weiser, Daniel A; Huwe, Peter J et al. (2014) ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26:682-94
Mossé, Yael P; Lim, Megan S; Voss, Stephan D et al. (2013) 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. Lancet Oncol 14:472-80
Carpenter, E L; Haglund, E A; Mace, E M et al. (2012) Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene 31:4859-67
Light, Jennifer E; Koyama, Hiroshi; Minturn, Jane E et al. (2012) Clinical significance of NTRK family gene expression in neuroblastomas. Pediatr Blood Cancer 59:226-32
Carpenter, Erica L; Mossé, Yael P (2012) Targeting ALK in neuroblastoma--preclinical and clinical advancements. Nat Rev Clin Oncol 9:391-9
Bresler, Scott C; Wood, Andrew C; Haglund, Elizabeth A et al. (2011) Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med 3:108ra114

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