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Combined autophagy and proteasome inhibition

Authors :
Daniel F. Heitjan
Thomas M. Paul
Janeen Kaplan
Laura Pontiggia
James E. Bradner
Lisa E. Davis
Emma C. Scott
Yunyoung C. Chang
Kay See Tan
Charles W. Nichols
Dan T. Vogl
David L. Porter
Gayle Mallon
Ravi K. Amaravadi
Shengfu Piao
Edward A. Stadtmauer
Reshma Rangwala
Source :
Autophagy. 10:1380-1390
Publication Year :
2014
Publisher :
Informa UK Limited, 2014.

Abstract

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

Details

ISSN :
15548635 and 15548627
Volume :
10
Database :
OpenAIRE
Journal :
Autophagy
Accession number :
edsair.doi.dedup.....11572d3867c26d032b58bfcf22e754a0
Full Text :
https://doi.org/10.4161/auto.29264