Vorinostat downregulates CD30 and decreases brentuximab vedotin efficacy in human lymphocytes

Zainul S. Hasanali, Elliot M. Epner, David J. Feith, Thomas P. Loughran, Clare Sample

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm.

Original languageEnglish (US)
Pages (from-to)2784-2792
Number of pages9
JournalMolecular cancer therapeutics
Volume13
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Down-Regulation
Lymphocytes
Therapeutics
Neoplasms
vorinostat
cAC10-vcMMAE
Drug Interactions
Pharmaceutical Preparations
Anti-Idiotypic Antibodies
Clinical Trials
Drug Therapy
Cell Line
Acids

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hasanali, Zainul S. ; Epner, Elliot M. ; Feith, David J. ; Loughran, Thomas P. ; Sample, Clare. / Vorinostat downregulates CD30 and decreases brentuximab vedotin efficacy in human lymphocytes. In: Molecular cancer therapeutics. 2014 ; Vol. 13, No. 12. pp. 2784-2792.
@article{f24dac755d024476a5c1e0beb1900ab8,
title = "Vorinostat downregulates CD30 and decreases brentuximab vedotin efficacy in human lymphocytes",
abstract = "With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50{\%} or more. Interestingly, low-dose SAHA treatment that maintained 50{\%} or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm.",
author = "Hasanali, {Zainul S.} and Epner, {Elliot M.} and Feith, {David J.} and Loughran, {Thomas P.} and Clare Sample",
year = "2014",
month = "12",
day = "1",
doi = "10.1158/1535-7163.MCT-14-0593",
language = "English (US)",
volume = "13",
pages = "2784--2792",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

Vorinostat downregulates CD30 and decreases brentuximab vedotin efficacy in human lymphocytes. / Hasanali, Zainul S.; Epner, Elliot M.; Feith, David J.; Loughran, Thomas P.; Sample, Clare.

In: Molecular cancer therapeutics, Vol. 13, No. 12, 01.12.2014, p. 2784-2792.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Vorinostat downregulates CD30 and decreases brentuximab vedotin efficacy in human lymphocytes

AU - Hasanali, Zainul S.

AU - Epner, Elliot M.

AU - Feith, David J.

AU - Loughran, Thomas P.

AU - Sample, Clare

PY - 2014/12/1

Y1 - 2014/12/1

N2 - With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm.

AB - With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm.

UR - http://www.scopus.com/inward/record.url?scp=84917694588&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84917694588&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-14-0593

DO - 10.1158/1535-7163.MCT-14-0593

M3 - Article

VL - 13

SP - 2784

EP - 2792

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 12

ER -