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Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo.

Abstract Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC50, cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC50:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.
PMID
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Authors

Mayor MeshTerms
Keywords

Epithelial ovarian carcinoma

HER2/neu

Neratinib

SCID mice

Journal Title medical oncology (northwood, london, england)
Publication Year Start




PMID- 28397106
OWN - NLM
STAT- MEDLINE
DA  - 20170411
DCOM- 20170414
LR  - 20170414
IS  - 1559-131X (Electronic)
IS  - 1357-0560 (Linking)
VI  - 34
IP  - 5
DP  - 2017 May
TI  - Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian
      carcinoma in vitro and in vivo.
PG  - 91
LID - 10.1007/s12032-017-0956-8 [doi]
AB  - Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies.
      There is a need to optimize the currently available treatment strategies and to
      urgently develop novel therapeutic agents against chemotherapy-resistant disease.
      The objective of our study was to evaluate neratinib's preclinical efficacy in
      treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating
      HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor
      cell lines with differential HER2/neu expression. Flow cytometry was utilized to 
      assess IC50, cell signaling changes, and cell cycle distribution. Neratinib's in 
      vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma
      xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified.
      Neratinib showed significantly higher efficacy in treating HER2/neu-amplified
      cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean +/-
      SEM IC50:0.010 muM +/- 0.0003 vs. 0.076 muM +/- 0.005 p &lt; 0.0001). Neratinib
      treatment significantly decreased the phosphorylation of the transcription factor
      S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged
      survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts
      (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression 
      and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro.
      Neratinib inhibits xenograft growth and improves overall survival in
      HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.
FAU - Menderes, Gulden
AU  - Menderes G
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Bonazzoli, Elena
AU  - Bonazzoli E
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Bellone, Stefania
AU  - Bellone S
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Black, Jonathan D
AU  - Black JD
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Lopez, Salvatore
AU  - Lopez S
AD  - Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome,
      Italy.
FAU - Pettinella, Francesca
AU  - Pettinella F
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Masserdotti, Alice
AU  - Masserdotti A
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Zammataro, Luca
AU  - Zammataro L
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Litkouhi, Babak
AU  - Litkouhi B
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Ratner, Elena
AU  - Ratner E
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Silasi, Dan-Arin
AU  - Silasi DA
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Azodi, Masoud
AU  - Azodi M
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Schwartz, Peter E
AU  - Schwartz PE
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA.
FAU - Santin, Alessandro D
AU  - Santin AD
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University
      School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT,
      06520-8063, USA. [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170410
PL  - United States
TA  - Med Oncol
JT  - Medical oncology (Northwood, London, England)
JID - 9435512
RN  - 0
      (N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(di
      methylamino)-2-butenamide)
RN  - 0 (Quinolines)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - Ovarian epithelial cancer
SB  - IM
MH  - Aged
MH  - Animals
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Female
MH  - Gene Amplification
MH  - Humans
MH  - Mice
MH  - Middle Aged
MH  - Neoplasms, Glandular and Epithelial/*drug therapy/enzymology/genetics/pathology
MH  - Ovarian Neoplasms/*drug therapy/enzymology/genetics/pathology
MH  - Quinolines/*pharmacology
MH  - Receptor, ErbB-2/*antagonists &amp; inhibitors/biosynthesis/genetics
MH  - Signal Transduction
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Epithelial ovarian carcinoma
OT  - HER2/neu
OT  - Neratinib
OT  - SCID mice
EDAT- 2017/04/12 06:00
MHDA- 2017/04/15 06:00
CRDT- 2017/04/12 06:00
PHST- 2017/03/13 [received]
PHST- 2017/04/08 [accepted]
AID - 10.1007/s12032-017-0956-8 [doi]
AID - 10.1007/s12032-017-0956-8 [pii]
PST - ppublish
SO  - Med Oncol. 2017 May;34(5):91. doi: 10.1007/s12032-017-0956-8. Epub 2017 Apr 10.

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