title: PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.
abstract: BACKGROUND
  Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer.
  
  
  METHODS
  PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models.
  
  
  RESULTS
  PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response.
  
  
  CONCLUSIONS
  Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer.
authors.affiliation: Mayo Clinic, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minnesota, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Winterhoff
authors.affiliation: Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Freyer
authors.affiliation: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.affiliation: Henry Ford Health System, Neurology Research, Detroit, MI, USA.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA.
authors.forename: Debarshi
authors.initials: D
authors.lastname: Roy
authors.affiliation: Mayo Clinic, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minnesota, USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Teoman
authors.affiliation: University of Minnesota, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minnesota, USA.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Mullany
authors.affiliation: Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hoffmann
authors.affiliation: Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: von Bismarck
authors.affiliation: Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, Kansas, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.affiliation: Mayo Clinic College of Medicine, Department of Medical Oncology, Minnesota, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Block
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital & University of Western Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.affiliation: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors.forename: Darryn
authors.initials: D
authors.lastname: Bampton
authors.affiliation: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors.forename: Keith
authors.initials: K
authors.lastname: Dredge
authors.affiliation: Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C557899:PG 545; D012503:Saponins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel; D002945:Cisplatin
keywords: HB-EGF; Heparanase; Ovarian cancer; PG545; Tumour microenvironment; VEGF