Abstract 1778: Antitumor effect of PM01183 in a patient-derived Cisplatin-sensitive and -resistant serous epithelial ovarian orthotopic tumor model

Abstract

Abstract Background: Epithelial ovarian cancer (EOC) is the leading cause of deaths in women diagnosed with gynecologic malignancies. The low survival rate is due to its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. As such, the development of effective innovative therapeutic strategies to overcoming cisplatin resistance remains a high priority. PM01183 is a new alkaloid that binds to the minor groove of DNA and induces delayed progression of S phase and cycle arrest in G2/M. Currently, PM01183 clinical development includes Phase II single agent trials (pancreas, breast and platinum-resistant/refractory ovarian) as well as Phase I trials in combination (with doxorubicin and gemcitabine) and in advanced acute leukemia. Here, we report that PM01183 is effective in the treatment of new developed orthotopic subject-derived epithelial serous ovarian tumor grafts Cisplatin-sensitive and-resitan models. Material and Methods: Athymic nude female mice were orthotopically engrafted with derived-fragments of OVAX1 (Cisplatin-Sensitive) or OVAX1R (Cisplatin-Resistant) tumors, and when tumors reached homogeneous palpable size were randomly allocated into the treatment groups (N = 8-12/group): i) Placebo; ii) PM01183 (0.18 mg/kg); iii) Cisplatin (3.5 mg/kg); and, iv) PM01183 plus Cisplatin (0.18+3.5 mg/kg). Drugs were intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and seven days after the last dose (Day 21), animals were sacrificed, their ovaries dissected-free and weighed. Statistical differences between groups were determined using two-tailed Mann-Whitney U test. Results: On day 21, OVA1X tumors experienced reductions of 95.3, 88.3 and 87.2% following the treatment with Cisplatin, PM01183 and PM01183+Cisplatin, respectively. The results obtained for OVA1XR tumor demonstrated tumor weight reductions of 48.2, 93.6 and 96.7% for Cisplatin, PM01183 and PM01183+Cisplatin treatments, respectively. Single therapy with PM01183 induced a statistically significant better response than Cisplatin (P=0.003). Also, PM01183+Cisplatin treatment increased the activity following Cisplatin (P=0.002) or PM01183 (P=0.022) administration as single agents, suggesting thus a synergistic effect of both compounds. Conclusions: PM01183 demonstrated strong in vivo antitumor activity in pure patient-derived Cisplatin-sensitive and Cisplatin-resistant serous epithelial ovarian orthotopic tumor models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1778. doi:1538-7445.AM2012-1778