Dataset Information

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia.

ABSTRACT: The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this "general response across drugs" (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.

SUBMITTER: White BS

PROVIDER: S-EPMC8302655 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia.

White Brian S BS Khan Suleiman A SA Mason Mike J MJ Ammad-Ud-Din Muhammad M Potdar Swapnil S Malani Disha D Kuusanmäki Heikki H Druker Brian J BJ Heckman Caroline C Kallioniemi Olli O Kurtz Stephen E SE Porkka Kimmo K Tognon Cristina E CE Tyner Jeffrey W JW Aittokallio Tero T Wennerberg Krister K Guinney Justin J

NPJ precision oncology 20210723 1

The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this "general response across d ...[more]

PMID: 34302041

Similar Datasets

Project description:BackgroundVenetoclax (VTX) is an anticancer drug. It is a selective Bcl-2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp-up schedule that is cumbersome in clinical situations.AimsTo overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)-drug conjugate of VTX (PEG-VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo.Methods and resultsVTX and 4-armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG-VTX selectively induced potent growth inhibition of MV4-11 human AML cells via the inducement of Bcl-2-mediated apoptosis. PEG-VTX had the effect of free VTX, presumably due to the protease-mediated release of VTX from the conjugates. In in vivo studies with AML tumor-xenograft mice models, intravenous PEG-VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15-30 times smaller for an OCI-AML-2 xenograft model and a dosing regimen that was less frequent for an MV4-11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX.ConclusionThe results of this study suggest that PEG-VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML.

Dataset Information

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia.

Publications

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets