PMID- 22700681
OWN - NLM
STAT- MEDLINE
DCOM- 20121031
LR  - 20211021
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 11
IP  - 7
DP  - 2012 Jul
TI  - Targeting the insulin growth factor and the vascular endothelial growth factor 
      pathways in ovarian cancer.
PG  - 1576-86
LID - 10.1158/1535-7163.MCT-11-0961 [doi]
AB  - Antiangiogenic therapy is emerging as a highly promising strategy for the 
      treatment of ovarian cancer, but the clinical benefits are usually transitory. 
      The purpose of this study was to identify and target alternative angiogenic 
      pathways that are upregulated in ovarian xenografts during treatment with 
      bevacizumab. For this, angiogenesis-focused gene expression arrays were used to 
      measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts 
      treated with bevacizumab or control. Reverse transcription-PCR was used for 
      results validation. The insulin growth factor 1 (IGF-1) was found upregulated in 
      tumor and stromal cells in the two ovarian xenograft models treated with 
      bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual 
      anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased 
      inhibition of tumor growth. Immunohistochemistry measured multivessel density, 
      Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl 
      transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in 
      ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased 
      tumor cell apoptosis in vivo compared with therapy targeting either individual 
      pathway. The combination blocked angiogenesis and cell proliferation but not more 
      significantly than each antibody alone. In summary, IGF-1 activation represents 
      an important mechanism of adaptive escape during anti-VEGF therapy in ovarian 
      cancer. This study provides the rationale for designing bevacizumab-based 
      combination regimens to enhance antitumor activity.
CI  - (c)2012 AACR.
FAU - Shao, Minghai
AU  - Shao M
AD  - Department of Medicine, Indiana University School of Medicine, Indianapolis, 
      Indiana 46202, USA.
FAU - Hollar, Stacy
AU  - Hollar S
FAU - Chambliss, Daphne
AU  - Chambliss D
FAU - Schmitt, Jordan
AU  - Schmitt J
FAU - Emerson, Robert
AU  - Emerson R
FAU - Chelladurai, Bhadrani
AU  - Chelladurai B
FAU - Perkins, Susan
AU  - Perkins S
FAU - Ivan, Mircea
AU  - Ivan M
FAU - Matei, Daniela
AU  - Matei D
LA  - eng
GR  - R01 CA155332/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120613
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 2285XW22DR (cixutumumab)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
SB  - IM
MH  - Angiogenesis Inhibitors/administration & dosage/pharmacology
MH  - Animals
MH  - Antibodies, Monoclonal/administration & dosage/pharmacology
MH  - Antibodies, Monoclonal, Humanized/administration & dosage/pharmacology
MH  - Antineoplastic Agents/administration & dosage/pharmacology
MH  - Apoptosis/drug effects
MH  - Bevacizumab
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Insulin-Like Growth Factor I/antagonists & inhibitors/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Ovarian Neoplasms/drug therapy/genetics/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Vascular Endothelial Growth Factor A/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC4497519
MID - NIHMS634800
COIS- Disclosure of Potential Conflicts of Interest: No potential conflicts of interest 
      were disclosed.
EDAT- 2012/06/16 06:00
MHDA- 2012/11/01 06:00
PMCR- 2015/07/09
CRDT- 2012/06/16 06:00
PHST- 2012/06/16 06:00 [entrez]
PHST- 2012/06/16 06:00 [pubmed]
PHST- 2012/11/01 06:00 [medline]
PHST- 2015/07/09 00:00 [pmc-release]
AID - 1535-7163.MCT-11-0961 [pii]
AID - 10.1158/1535-7163.MCT-11-0961 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2012 Jul;11(7):1576-86. doi: 10.1158/1535-7163.MCT-11-0961. Epub 
      2012 Jun 13.