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Neuroblastoma (NB) is a malignancy arising from the developing sympathetic nervous system that typically presents in early childhood. The majority of high-risk patients die despite intensive cytotoxic therapies and survivors are burdened with treatment-related co-morbidities. The Mossé Lab has steadfastly focused on this disease, in particular on the broad hypothesis that discovery of the genetic basis of NB will provide insights that are clinically actionable and will improve outcomes.
Despite an exponential increase in discoveries related to NB genetics and immune evasion, a child diagnosed with NB today is subjected to a largely empiric and highly intensive regimen of genotoxic chemotherapeutics, radiation therapy, and a new immunotherapy that while effective, has significant side effects including excruciating pain. The Mossé Lab seeks to change this paradigm by developing and implementing biomarker-directed precision therapeutics.
The lab identified activating point mutations within the tyrosine kinase domain of the Anaplastic Lymphoma Kinase (ALK) gene as the major cause of hereditary NB, and the lab and others showed that these same alterations are the most common somatic single nucleotide mutations in the sporadic forms of the disease. The lab has subsequently showed that for ALK-driven NBs, primary resistance to ALK inhibition therapy is a major obstacle. Presently, ALK is the only mutated oncogene tractable for targeted therapy in NB, and the lab has made significant progress toward improving patient outcomes with ALK-directed therapy over the last decade, including:
- A now completed phase 2 clinical trial of the ALK inhibitor crizotinib in children with ALK-driven malignancies (ADVL0912)
- Development and implementation of a clinical trial matching genomic aberrations at the time of relapse to rationally designed combinations of molecularly targeted agents (NEPENTHE)
- Identification of lorlatinib as the only ALK inhibitor that is effective against all activating mutations and rapidly opened a phase 1 clinical trial (NANT2015-02)
- Demonstration that chemotherapy could sensitize ALK mutant NBs to crizotinib, leading to a pivotal phase 3 trial (ANBL1531) of ALK inhibition therapy for patients newly diagnosed with NB
Furthermore, the lab’s studies have revealed that native ALK protein is expressed on the surface of the majority of NB cells, but not on normal tissue, providing an opportunity for the development of immune-targeting strategies with potential application to other pediatric solid tumors.
- Genetic susceptibility to NB: This is an area of active investigation in the Mossé Lab, with a specific focus on elucidating the genotype-phenotype correlations to develop evidence-based guidelines for genetic counseling; identifying genetic modifiers of disease phenotype and penetrance in individuals and families with a germline ALK mutation; and identifying other NB-associated predisposition variants – all of which will have wide-ranging implications for furthering the understanding of NB biology and therapy, and will allow clinicians to best counsel patients and develop efficacious and sound surveillance strategies.
- Defining and exploiting subclonal heterogeneity: NBs are extensively heterogeneous, such that patients being considered for targeted therapies may either already possess resistance to the drug, or alternatively, may only harbor the molecular vulnerability in a minority of cells. The Mossé Lab has developed a novel NB-specific ultra-deep sequencing platform and bioinformatics pipeline to assay for these mutations, even when present at very low level. The lab will extend this tissue-based diagnostic to the development of a blood-based assay that will allow for a noninvasive “liquid biopsy” method to capture tumor cell DNA for sequencing, and as a means to assess response to therapy, as well as emergence and mechanisms of early disease recurrence.
- Identifying therapeutic vulnerabilities imparted by inhibition of oncogenic ALK-RAS-MAPK signaling for biomarker-defined therapy: The Mossé Lab has set out to address the kinome activation state of ALK- and RAS-mutant NB cells in order to identify new combinatorial targets. The lab hypothesizes that SHP2 signaling is a critical vulnerability in both ALK and RAS-driven NBs and that SHP2 inhibition with lorlatinib, and SHP2 inhibition with trametinib, will sensitize receptor tyrosine kinase-driven NB cells and allow for a synergistic cytotoxic effect. The overarching objective of this work is to garner the preclinical justification required to move combination therapies to the clinic as part of the NExt-generation PErsonalized Neuroblastoma THErapy trial (NEPENTHE, NCT02780128). This umbrella trial will evolve with our basic and translational research insights, both in terms of targets currently being studied, but also as new targets/strategies are defined.
- Defining novel immunotherapeutic targets and strategies: The lab has shown that NBs aberrantly express ALK on the cell surface independent of mutation status, with scant expression on normal tissues, giving it the properties amenable to immunotherapeutic targeting. The lab recently recognized that ALK mRNA is differentially expressed in subsets of other childhood solid tumors, suggesting that ALK protein is a promising target for immunotherapy across several pediatric cancers. As such, the lab team has devoted a significant effort to validating and exploiting ALK as an immunotherapeutic target.
Co-Leader, Genes, Genomics, and Pediatric Disease Research Affinity Group
Dr. Mossé's research goal is to improve cure rates for the childhood cancer neuroblastoma by discovering the genetic basis of the disease and translating rational therapeutic opportunities to the clinic. She studies the contribution of DNA sequence variations and activation mutations of anaplastic lymphoma kinase (ALK) genes on the development and progression of both inherited and acquired forms of neuroblastoma.