Boris Winterhoff1, Luisa Freyer2, Edward Hammond3, Shailendra Giri4, Susmita Mondal2, Debarshi Roy2, Attila Teoman1, Sally A Mullany5, Robert Hoffmann2, Antonia von Bismarck2, Jeremy Chien6, Matthew S Block7, Michael Millward8, Darryn Bampton3, Keith Dredge3, Viji Shridhar2. 1. Mayo Clinic, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minnesota, USA. 2. Mayo Clinic College of Medicine, Department of Experimental Pathology, Minnesota, USA. 3. Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia. 4. Henry Ford Health System, Neurology Research, Detroit, MI, USA. 5. University of Minnesota, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Minnesota, USA. 6. Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, Kansas, USA. 7. Mayo Clinic College of Medicine, Department of Medical Oncology, Minnesota, USA. 8. Department of Medical Oncology, Sir Charles Gairdner Hospital & University of Western Australia.
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. CONCLUSION: Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer.
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 cancerpatients which might represent a potential biomarker of response. CONCLUSION: Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer.
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