9 research outputs found
Effects of cyclopiazonic acid and dexamethasone on serotonin-induced calcium responses in vascular smooth muscle cells
INCREASED VASCULAR SELECTIVITY AND PROLONGED PHARMACOLOGICAL EFFICACY OF THE L-TYPE Ca2+ CHANNEL ANTAGONIST LERCANIDIPINE IN HUMAN CARDIOVASCULAR TISSUE
PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120
Background Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43.7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6:: RUNX1-like (8.9%), MEF2D-rearranged (2.2%) or KMT2A-like (1.5%). A poor prognosis was associated with the Ph -like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54.4% of Ph-like compared to 16.2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH(1)8A(1), IKZF(1), CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nin-tedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xeno-graft model, showing a synergistic effect with dexamethasone. Interpretation This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Copyright (C) 2022 The Author(s). Published by Elsevier B.V