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Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab.

Abstract Trastuzumab, a therapeutic monoclonal antibody directed against ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab improved outcomes for many patients with ErbB2-positive breast and gastric cancers, however, cardiac side effects [e.g., left ventricular dysfunction and congestive heart failure (CHF)] were reported in the early phase clinical studies. This finding, subsequently corroborated by multiple clinical studies, raised concerns that the observed cardiotoxicity induced by trastuzumab might adversely impact the clinical development of other therapeutics targeting ErbB family members. Areas covered: In this review we summarize both basic research and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if there has been an impact of trastuzumab-induced cardiotoxicity on the development of other agents targeting ErbB family members. Expert opinion: There are a number of scientific gaps that are critically important to address for the continued success of HER2-targeted agents. These include: 1) elucidating the molecular mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical testing systems for predicting cardiotoxicity; 3) developing clinical strategies to identify patients at risk of cardiotoxicity; and 4) enhancing management of clinical symptoms of cardiotoxicity.
PMID
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Authors

Mayor MeshTerms
Keywords

ErbB2-targeted therapies

HER2/ErbB2-positive breast cancer

HER2/ErbB2-targeted therapy

cardiotoxicity

drug development

trastuzumab

Journal Title expert opinion on drug metabolism & toxicology
Publication Year Start




PMID- 28571477
OWN - NLM
STAT- MEDLINE
DCOM- 20170726
LR  - 20170726
IS  - 1744-7607 (Electronic)
IS  - 1742-5255 (Linking)
VI  - 13
IP  - 7
DP  - 2017 Jul
TI  - Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a 
      spotlight on trastuzumab.
PG  - 755-766
LID - 10.1080/17425255.2017.1337746 [doi]
AB  - INTRODUCTION: Trastuzumab, a therapeutic monoclonal antibody directed against
      ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab
      improved outcomes for many patients with ErbB2-positive breast and gastric
      cancers, however, cardiac side effects [e.g., left ventricular dysfunction and
      congestive heart failure (CHF)] were reported in the early phase clinical
      studies. This finding, subsequently corroborated by multiple clinical studies,
      raised concerns that the observed cardiotoxicity induced by trastuzumab might
      adversely impact the clinical development of other therapeutics targeting ErbB
      family members. Areas covered: In this review we summarize both basic research
      and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if 
      there has been an impact of trastuzumab-induced cardiotoxicity on the development
      of other agents targeting ErbB family members. Expert opinion: There are a number
      of scientific gaps that are critically important to address for the continued
      success of HER2-targeted agents. These include: 1) elucidating the molecular
      mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical
      testing systems for predicting cardiotoxicity; 3) developing clinical strategies 
      to identify patients at risk of cardiotoxicity; and 4) enhancing management of
      clinical symptoms of cardiotoxicity.
FAU - Dokmanovic, Milos
AU  - Dokmanovic M
AD  - a Division of Biotechnology Review and Research I, Office of Biotechnology
      Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and
      Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA.
FAU - King, Kathryn E
AU  - King KE
AD  - a Division of Biotechnology Review and Research I, Office of Biotechnology
      Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and
      Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA.
FAU - Mohan, Nishant
AU  - Mohan N
AD  - a Division of Biotechnology Review and Research I, Office of Biotechnology
      Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and
      Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA.
FAU - Endo, Yukinori
AU  - Endo Y
AD  - a Division of Biotechnology Review and Research I, Office of Biotechnology
      Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and
      Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA.
FAU - Wu, Wen Jin
AU  - Wu WJ
AD  - a Division of Biotechnology Review and Research I, Office of Biotechnology
      Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and
      Research , U.S. Food and Drug Administration , Silver Spring , MD 20993 , USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20170609
PL  - England
TA  - Expert Opin Drug Metab Toxicol
JT  - Expert opinion on drug metabolism & toxicology
JID - 101228422
RN  - 0 (Antineoplastic Agents)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*adverse effects/pharmacology
MH  - Breast Neoplasms/drug therapy/pathology
MH  - Cardiotoxicity/*etiology/physiopathology
MH  - Drug Design
MH  - Drug Evaluation, Preclinical/methods
MH  - Female
MH  - Humans
MH  - Molecular Targeted Therapy
MH  - Receptor, ErbB-2/antagonists & inhibitors
MH  - Stomach Neoplasms/drug therapy/pathology
MH  - Trastuzumab/administration & dosage/*adverse effects/pharmacology
OTO - NOTNLM
OT  - ErbB2-targeted therapies
OT  - HER2/ErbB2-positive breast cancer
OT  - HER2/ErbB2-targeted therapy
OT  - cardiotoxicity
OT  - drug development
OT  - trastuzumab
EDAT- 2017/06/03 06:00
MHDA- 2017/07/27 06:00
CRDT- 2017/06/03 06:00
PHST- 2017/06/03 06:00 [pubmed]
PHST- 2017/07/27 06:00 [medline]
PHST- 2017/06/03 06:00 [entrez]
AID - 10.1080/17425255.2017.1337746 [doi]
PST - ppublish
SO  - Expert Opin Drug Metab Toxicol. 2017 Jul;13(7):755-766. doi:
      10.1080/17425255.2017.1337746. Epub 2017 Jun 9.