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Harnessing clonal evolution in chronic lymphocytic leukemia

Objective

Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is addicted of interactions with the microenvironment. The B-cell receptor (BCR) is one of the most important surface molecules that CLL cells use to gain oncogenic signals from the microenvironment. The critical role of BCR signaling for the pathogenesis of CLL is supported by the therapeutic success of ibrutinib, a targeted agent that disrupts the BCR pathway. Beside microenvironment-promoted oncogenic signals, the biology of CLL is also driven by molecular lesions and clonal evolution, that mark CLL progression and treatment resistance. The interconnection between microenvironment-promoted oncogenic signals and clonal evolution has been postulated in CLL but never proven because of the lack of suitable ex vivo models. Ibrutinib allows the unprecedented opportunity of assessing the contribution of cell signaling to cancer clonal evolution directly in vivo in patients. The project working hypothesis is that mutation- and selection-driven clonal evolution is promoted by microenvironment-induced signals, including those propagated from the BCR. According to this hypothesis: i) BCR signaling inhibition due to ibrutinib should stop clonal evolution; while ii) acquisition of by-pass mechanisms that keep ongoing signaling should promote mutation and selection despite BCR inhibition, thus favoring CLL clonal evolution and ibrutinib resistance. In this scenario, the combination of ibrutinib with drugs that overcome by-pass mechanisms could prevent clonal evolution, thus improving treatment efficacy and patient outcome. In order to address our working hypothesis, we will take advantage of clinical trial and co-clinical trial samples to monitor signaling and clonal evolution under ibrutinib and ibrutinib-based combination treatments.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /medical and health sciences/clinical medicine/oncology/leukemia
  • /natural sciences/biological sciences/cell biology/cell signaling

Call for proposal

ERC-2017-COG
See other projects for this call

Funding Scheme

ERC-COG - Consolidator Grant

Host institution

FONDAZIONE PER L'ISTITUTO ONCOLOGICO DI RICERCA (IOR)
Address
Via Vincenzo Vela 6
6500 Bellinzona
Switzerland
Activity type
Research Organisations
EU contribution
€ 1 940 000

Beneficiaries (1)

FONDAZIONE PER L'ISTITUTO ONCOLOGICO DI RICERCA (IOR)
Switzerland
EU contribution
€ 1 940 000
Address
Via Vincenzo Vela 6
6500 Bellinzona
Activity type
Research Organisations