Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma

Abstract

We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (n = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.

Functional MRI Measurements to Predict Early Adenoviral Gene Therapy Response in Ovarian Cancer Mouse Model

“…These results are in line with our previous studies with adenoviral gene therapy with sVEGFR-1, sVEGFR-2 and sVEGFR-3 and a clinical study is warranted [27,29]. Survival was significantly prolonged in treatment group II as compared to control group I and other treatment groups (III, IV).…”

“…As in our previous studies [27][28][29] morphologic MRI was used for the timing of gene therapy to treat sizeable tumors, not a micrometastatic disease. Furthermore, non-invasive DW-MRI and relaxation time measurements were used to monitor treatment responses at molecular level in several time points in solid ovarian cancer tumors.…”

Soluble Vascular Endothelial Growth Factor Receptor-1 Improves Therapeutic Efficacy of Suicide Gene Therapy in an Angiogenesis-Independent Manner

“…Thus far, AdHSV-tk/GCV and AdsVEGFR-1 gene therapies have not been combined for the treatment of MG or any other cancer. AdHSV-tk/GCV has been successfully combined with endostatin gene therapy for the treatment of renal cell cancer (Pulkkanen et al, 2002), while sVEGFR-1 has been combined with oncolytic viruses (Zhang et al, 2005;Guse et al, 2010), other sVEGFRs (Sallinen et al, 2009), soluble Tie2 (Sallinen et al, 2011), and chemotherapy (Sopo et al, 2012). All previous studies with sVEGFR-1 gene therapy for MG were conducted on nude mouse models.…”

“…/hum.2013 (Graepler et al, 2005) has shown synergy with sVEGFR-1. Our group has previously demonstrated successful combination of soluble VEGF receptors 1, 2, and 3 (Sallinen et al, 2009;Sopo et al, 2012), and 1 and 3 (Sallinen et al, 2011) with soluble Tie-2 in an ovarian cancer model. Combination with cytotoxic therapy could possibly overcome some of the inherent drawbacks of anti-angiogenic therapy, mentioned before.…”

“…In most of these studies, the efficacy was evaluated as a monotherapy. A few studies have combined sVEGFR-1 with chemotherapies such as 5-FU (Zhang et al, 2005), cisplatin (Gao et al, 2007), and paclitaxel (Sopo et al, 2012), and oncolytic virotherapy. Combination with other anti-angiogenic agents 1 Department of Biotechnology and Molecular Medicine, A.I.…”