Targeting pericytes with a PDGF-B aptamer in human ovarian carcinoma models.
OBJECTIVE
On the basis of the known role of platelet-derived growth factor (PDGF)-BB/PDGF receptor (PDGFR) beta in pericyte regulation, highly specific inhibitors of this target are needed. We tested the efficacy of a highly selective aptamer against PDGF-B with or without anti-VEGF therapy in ovarian cancer models.


RESULTS
Bevacizumab inhibited tumor growth by 45% and 48% in the HeyA8 and SKOV3ip1 models, respectively. AX102 had minimal effect on the HeyA8 model, but increased tumor growth in the SKOV3ip1 model. However, bevacizumab plus AX102 was more effective than bevacizumab alone, and resulted in 76-88% inhibition of tumor growth in both models. A longitudinal study in the HeyA8 model using bioluminescence imaging showed that combination of bevacizumab, AX102 and paclitaxel caused tumor reduction by 65% (based on bioluminescence imaging). In the HeyA8 model, MVD and PCNA counts were significantly reduced in the bevacizumab treatment groups, and pericyte coverage was significantly decreased in the AX102 treatment groups. In the SKOV3ip1 model, MVD and PCNA was significantly reduced in the bevacizumab treatment group, and even lower in the bevacizumab and AX102 combination treatment group.


METHODS
The therapeutic efficacy of targeting endothelial cells (bevacizumab) and/or pericytes (PDGF-aptamer, AX102) was examined using HeyA8 and SKOV3ip1 orthotopic models of ovarian cancer metastasis. Following therapy, tumors were examined for microvessel density (MVD), proliferating cell nuclear antigen (PCNA) and vascular maturation (pericyte coverage).


CONCLUSIONS
Dual targeting of endothelial cells and pericytes holds potential as an anti-vascular therapeutic approach in ovarian carcinoma.
Lu
Chunhua
C
Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, Houston, TX, USA.
Shahzad
Mian M K
MM
Moreno-Smith
Myrthala
M
Lin
Yvonne G
YG
Jennings
Nicholas B
NB
Allen
Julie K
JK
Landen
Charles N
CN
Mangala
Lingegowda S
LS
Armaiz-Pena
Guillermo N
GN
Schmandt
Rosemarie
R
Nick
Alpa M
AM
Stone
Rebecca L
RL
Jaffe
Robert B
RB
Coleman
Robert L
RL
Sood
Anil K
AK
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D000068258:Bevacizumab; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008137:Longitudinal Studies; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D017239:Paclitaxel