Dataset Information

Repurposing dasatinib for diffuse large B cell lymphoma.

ABSTRACT: To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

SUBMITTER: Scuoppo C

PROVIDER: S-EPMC6708382 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Repurposing dasatinib for diffuse large B cell lymphoma.

Scuoppo Claudio C Wang Jiguang J Persaud Mirjana M Mittan Sandeep K SK Basso Katia K Pasqualucci Laura L Rabadan Raul R Inghirami Giorgio G Grandori Carla C Bosch Francesc F Dalla-Favera Riccardo R

Proceedings of the National Academy of Sciences of the United States of America 20190805 34

To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib r ...[more]

PMID: 31383760

Similar Datasets

Project description:BackgroundDiffuse large B-cell lymphoma (DLBCL) constitutes 30% of all non-Hodgkin's lymphomas. It can present as a nodal disease or as an extra nodal disease. Based on the site of origin, extra nodal DLBCL (EN-DLBCL) may have a distinct clinical outcome. Apart from the site of origin, factors including demographics, stage, and presence of any other primary malignancy also affect the outcome. The purpose of our study was to characterize prognostically distinct groups based on the site of presentation of EN-DLBCL.MethodsWe used 18 registries in Surveillance, Epidemiology, and End Results database to identify the patients with EN-DLBCL for 2000 - 2015 with last follow-up till December 31, 2018. A total of 30,290 EN-DLBCL patients were selected and categorized based on 13 broad sites grouping. Demographic variables were summarized. We did overall survival analysis with univariate and multivariate Cox-proportional hazard modeling. Short-term survival trend was calculated as well.ResultsThe percentage of EN-DLBCL of all DLBCLs is 34.48%. EN-DLBCL was comparatively seen more in males (54.94%) and non-Hispanic whites (71.52%). In terms of clinical characteristics, patients with EN-DLBCL were mostly diagnosed at age ≥ 60 years (66.11%), early stage (69.33%), and presentation as first primary cancer (81.89%). A higher risk of mortality was seen in non-Hispanic black (hazard ratio (HR) 1.36), with late age of onset (HR 2.69), late stage at presentation (HR 1.42), and with history of other malignancy (HR 1.29). Compared to the intestinal tract, the risk of overall mortality was higher in individuals with involvement of nervous system (HR 1.85), pancreas and hepatobiliary system (HR 1.22), and respiratory system (HR 1.18) and the best outcomes were seen in heart and mediastinal site (HR 0.58) of DLBCL.ConclusionBased upon our population-based study, we conclude that primary site of presentation of EN-DLBCL is an important prognostic factor with significant difference in survival based on histological and epidemiological characteristics.

Dataset Information

Repurposing dasatinib for diffuse large B cell lymphoma.

Publications

Repurposing dasatinib for diffuse large B cell lymphoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets