PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples. Issue 7 (May 2015)

• Record Type: Journal Article
• Authors: Winterhoff, Boris; Freyer, Luisa; Hammond, Edward; Giri, Shailendra; Mondal, Susmita; Roy, Debarshi; Teoman, Attila; Mullany, Sally A.; Hoffmann, Robert; von Bismarck, Antonia; Chien, Jeremy; Block, Matthew S.; Millward, Michael; Bampton, Darryn; Dredge, Keith; Shridhar, Viji
• Is Part Of: European journal of cancer. Volume 51:Issue 7(2015:May)
• Page Start: 879
• Page End: 892
• Publication Date: 2015-05
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2015.02.007
• Languages: English
• ISSNs: 0959-8049

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title id="st190">Abstract</title> <sec> <title id="st145">Background</title> <p id="sp0005">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.</p> </sec> <sec> <title id="st150">Methods</title> <p id="sp0010">PG545's anti-cancer activity was investigated <italic>in vitro</italic> and <italic>in vivo</italic> as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models.</p> </sec> <sec> <title id="st155">Results</title> <p id="sp0015">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 <italic>in vitro</italic> 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 <italic>in vivo</italic>. 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.</p> </sec> <sec> <title id="st160">Conclusion</title> <p id="sp0020">Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer.</p> </sec> </abstract>