Combined therapy with thrombospondin-1 type I repeats (3TSR) and chemotherapy induces regression and significantly improves survival in a preclinical model of advanced stage epithelial ovarian cancer.
Most women are diagnosed with epithelial ovarian cancer (EOC) at advanced stage, where therapies have limited effectiveness and the long-term survival rate is low. We evaluated the effects of combined antiangiogenic and chemotherapy treatments on advanced stage EOC. Treatment of EOC cells with a recombinant version of the thrombospondin-1 type I repeats (3TSR) induced more apoptotic cell death (36.5 ± 9.6%) in vitro compared to untreated controls (4.1 ± 1.4). In vivo, tumors were induced in an orthotopic, syngeneic mouse model of advanced stage EOC. Mice were treated with 3TSR (4 mg/kg per day) alone or in combination with chemotherapy drugs delivered with maximum tolerated dose or metronomic scheduling. Pretreatment with 3TSR induced tumor regression, normalized tumor vasculature, and improved uptake of chemotherapy drugs. Combination 3TSR and metronomic chemotherapy induced the greatest tumor regression (6.2-fold reduction in size compared to PBS-treated controls) and highest survival when treatment was initiated at advanced stage. 3TSR binding to its receptor, CD36 (cluster of differentiation 36), increased binding of CD36 and SHP-1, which significantly inhibited phosphorylation of the VEGF receptor. In this study, we describe a novel treatment approach and mechanism of action with 3TSR and chemotherapy that induces regression of advanced stage EOC and significantly improves survival.-Russell, S., Duquette, M., Liu, J., Drapkin, R., Lawler, J., Petrik, J. Combined therapy with thrombospondin-1 type I repeats (3TSR) and chemotherapy induces regression and significantly improves survival in a preclinical model of advanced stage epithelial ovarian cancer.
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada; and.
Samantha
S
Russell
Beth Israel Deaconess Medical Center and.
Mark
M
Duquette
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Joyce
J
Liu
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Ronny
R
Drapkin
Beth Israel Deaconess Medical Center and.
Jack
J
Lawler
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada; and jpetrik@uoguelph.ca.
Jim
J
Petrik
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D000860:Hypoxia; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000401:mortality* / Q000628:therapy*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000494:pharmacology*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018955:CD36 Antigens; D019700:Thrombospondin 1; D040262:Receptors, Vascular Endothelial Growth Factor; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
antiangiogenic; metronomic; vessel normalization