Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis

Frontiers in Cardiovascular Medicine

Michael G. Fradley¹  Nida Waheed²  Rachid C. Baz³  Timothy J. Garrett⁴  Lihui Yuan⁵  Sonal Singh⁶  Marwa Tantawy⁶  Lakshmi Manasa Chekka⁶  Yimei Huang⁶  Taimour Langaee⁷  Yan Gong⁸  Carl J. Pepine⁹  Keith March⁹  Chintan P. Shah^1,10  Robert F. Cornell^1,11  Jan S. Moreb^1,12  David L. DeRemer^1,13 

[1] Cardio-Oncology Center of Excellence, Division of Cardiology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States;Department of Internal Medicine, College of Medicine, University of Florida, Gainesville, FL, United States;Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States;Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States;Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States;Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, United States;Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, United States;Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, United States;Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, United States;UF Health Cancer Center, Gainesville, FL, United States;Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, United States;Division of Cardiovascular Medicine, Department of Medicine and Center for Regenerative Medicine, University of Florida, Gainesville, FL, United States;Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL, United States;Division of Hematology and Oncology, Vanderbilt University Medical Center, Preston Research Building, Nashville, TN, United States;Novant Health Forsyth Medical Center, Hematology, Transplantation, and Cellular Therapy Division, Winston-Salem, NC, United States;UF Health Cancer Center, Gainesville, FL, United States;

关键词: proteasome inhibitors;    Cardio-oncology;    carfilzomib;    metabolomcis;    proteomic;   

DOI  :  10.3389/fcvm.2021.645122

来源: Frontiers

【 摘 要 】

Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.

【 授权许可】

CC BY