Abstract 1: The novel heparin sulfate (HS) mimetic PG545 shows strong synergism when combined with cisplatin and paclitaxel in preclinical ovarian cancer models

1: The novel heparin sulfate (HS) mimetic PG545 shows strong synergism when combined with cisplatin and paclitaxel in preclinical ovarian cancer models B. Winterhoff, L. Freyer, A. Teoman, A. von Bismarck, K. Dredge, V. Shridhar. Mayo Clinic, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Rochester, MN, USA, Progen Pharmaceuticals Ltd, Brisbane, Australia, Mayo Clinic College of Medicine, Department of Experimental Pathology, Rochester, MN, USA Objectives: The majority of patients with ovarian cancer have recurrence of disease despite surgical debulking and adjuvant chemotherapy. The dual angiogenesis/metastasis inhibitor PG545 acts through interference with heparin-binding growth factors and through the inhibition of heparanase activity which leads to antitumor activity. Here we tested PG545 as a maintenance therapy as single agent or in addition to standard chemotherapy in ovarian cancer in vivo and in vitro. Methods: The luciferase-expressing human ovarian cancer cell line A2780 was used to establish mice xenografts. Mice, treated with 3 cycles of platinumand taxane-based chemotherapy, were compared to mice, additionally receiving PG545 as a maintenance agent from Day 3 and Day 10 on and PG545 as a single agent. Tumor growth was measured radiographically using the IVIS200 system. Tumors were stained with IHC for Ki67 and CD31. Western blots were performed for the Cancer stem cell marker Oct4 and Nanog. The anti-tumor efficacy of PG545 was further investigated in vitro in the ovarian cancer cell lines A2780 and SKOV3. MTT assay was used to determine the cytotoxic effect and anoikis assay to determine the effect of PG545 in a 3-dimensional culture system. Results: Untreated mice had a mean survival of 23 days. 70% of mice treated with Cisplatin and Paclitaxel relapsed after initial radiographic response and had a mean survival of 46 days. 90% of mice treated with PG545 had tumors with a mean survival of 41 days. 40% of mice treated with Cisplatin, Paclitaxel and PG545 on day 10 had tumor recurrence with a mean survival of 58 days. 100% of mice, receiving initial Cisplatin and Paclitaxel plus PG545 from Day 3 on survived until the end of the study (Day 63) and only 1 out of 10 mice showed a recurrent of a non-life threatening tumor. IHC stains revealed decrease in Ki67 and CD31 positive cells in tumors from the PG treated mice compared to the control and the Cisplatin Paclitaxel group. PG545 treated mice had significant reduction in cancer stem cell marker Oct-4, compared to the Cisplatin/Taxol group. Furthermore PG545 showed a cytotoxic effect in both MTT assay and the 3-dimensional culture system. Conclusions: The addition of the HS-mimetic PG545 to standard chemotherapy inhibits recurrence and significantly prolonged the progression-free and overall survival in our in vivo ovarian cancer model, which might be explained by reduction of neoangiogenesis and cancer stem cells. These observations provide biologic rational to test PG545 as a single agent or in combination with chemotherapy in