The FANTOM Doctoral Network (DN) (
https://fantom-project.eu(se abrirá en una nueva ventana)) consists of key members of the European research initiative for ALK related malignancies (ERIA) and the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL), a consortium of clinicians (n=46), pathologists (n=24), biologists (n=22) and trials coordinators (n=5) that collectively conduct research into childhood NHL. Employing these two networks and the significant resources within, the FANTOM DN is training and educating 10 talented researchers. Training, centred on interactions between companies and academic institutions, is taking the form of multiple scientific and clinical disciplines in order to explore the biology of childhood NHL to develop quality-controlled assays for stratification biomarkers and novel therapeutic strategies. In particular, we are focussing on a specific form of NHL, Anaplastic Large Cell Lymphoma (ALCL) which largely affects children and young adults specifically when associated with aberrant expression of anaplastic lymphoma kinase (ALK). Whilst overall survival is relatively high for childhood ALCL, 30% of children relapse, they still suffer the long-term side-effects of therapy and for some children, we are likely over-treating. This situation can only be improved if fundamental and clinical science is performed to identify less-toxic therapies guided by (non-invasive) biomarkers. With this in mind, our integrated programme is pursuing the following objectives:
Objective 1: Increase our understanding of the biological mechanisms, including the role of the immune system in ALCL, to inform on novel, less toxic therapeutic targets
The pathogenesis of ALCL is for the most part poorly elucidated with the mechanisms giving rise to this malignancy being little understood. However, the cell of origin of ALCL is postulated as an early thymic progenitor in which the driving oncogenic event, expression of the t(2;5) breakpoint product facilitates the acquisition of cancer hallmarks to incipient cancer cells. We are investigating this process further with a specific emphasis on the contributory role of the immune system and inflammatory signalling pathways. Employing a variety of model systems ranging from Genetically Engineered Mouse Models (GEMM) through to Patient Derived Xenografts (PDX), organoids, primary patient tumour material and cell lines, together with multiple omics technologies, we are studying the pathways that drive tumour growth, as well as the role of inflammatory cells with the aim of using these data to inform on novel therapeutic strategies and biomarkers for disease monitoring.
Objective 2: Apply our findings from the biology of ALCL to develop biomarkers for clinical translation
Primary patient tumours are being assessed for the status of their genomes, such as the presence of acquired mutations that may contribute to tumour growth using multiple omics technologies at a single cell level. In particular, single cell (sc) RNAseq, spatial transcriptomics, CyTOF, analysis of the epigenome and sc cDNA genotyping is being applied to develop prognostic algorithms. We are also assessing plasma components including exosomal small RNA (sRNA) species, circulating tumour DNA (ctDNA) and circulating antibodies to ALK. These data will be correlated to clinical data in order to identify at least 2 potential biomarkers for further clinical development, as well as to determine therapeutic targets in a personalised genomics approach.
Objective 3: Uncover mechanisms and origins of resistance of ALCL to therapy with tyrosine kinase inhibitors in order to identify novel therapeutic targets and develop a personalised therapeutic strategy
Relapse/refractory (r/r) disease is one of the major clinical problems and occurs both after chemotherapy, and targeted agents are employed in the clinic. To understand the mechanisms of resistance, we are employing scRNAseq, spatial transcriptomics and CRISPR screens towards the development of rescue therapies and/or therapeutic approaches that prevent r/r disease from occurring. Employing a variety of model systems from cell lines rendered resistant to targeted therapeutics through to PDX models of relapse and primary relapse tumour material, posited resistance mechanisms are being validated and assessed.
