Líneas de investigación

• Characterization of the functional impact of driver mutations and the analysis of new potential therapeutic approaches

  Genetic studies have led to the identification of novel recurrent somatic mutations with predicted functional impact, offering new potential therapeutic approaches. We are interested in the characterization of in vitro and in vivo cellular responses of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells to specific inhibitors against the most relevant recurrent mutations. Precisely, we are characterizing mutations in genes regulating RNA maturation (SF3B1, and other novel mutations of spliceosome), NOTCH1 signaling (NOTCH1), Toll-like receptor signaling (MYD88) and the RAS-BRAF-MAPK-ERK pathway.

• Development of predictive models recapitulating tumor heterogeneity and their impact on disease evolution, therapy resistance and susceptibility to novel targeted therapies

  Due to the high heterogeneity and complexity of B lymphoid malignancies, the analysis of the effect of novel targeted drugs in different mutational contexts is challenging. Moreover, there is no single gene mutation responsible for disease onset but a number of them affecting different pathways. Furthermore, most recurrent mutations are present in less than 5% of the patients and these mutations can be either clonal or sub-clonal. Thus, to capture this disease heterogeneity in preclinical models, the best approach is the generation of patient-derived xenografts (PDXs) models, together with modified cell lines, thus recapitulating the recurrent genetic alterations in CLL and MCL. These models constitute bona fide tools to analyze sensitivity/resistance to drugs.

• Mechanisms of resistance to targeted therapy

  Treatment with novel targeted drugs like the Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib or the Bcl-2 antagonist venetoclax improved outcome for CLL patients considerably. However, resistance to therapy is increasingly observed and remains an urgent clinical need. Using in vitro and in vivo models, we are characterizing the mechanisms of response and resistance to targeted treatments (ibrutinib and venetoclax) in the context of specific driver mutations and  disease microenvironment to find new potential therapeutic combinations.