Abstract A173: The new marine derived tubulin binding agent PM060184 shows potent antitumor activity in vivo against multidrug resistant, Pgp expressing tumors.

Abstract

Abstract PM060184 is new marine derived tubulin-binding agent originally isolated from the sponge Lithoplocamia lithistoides. The compound is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases. PM060184 showed potent antitumor activity in vitro and also in vivo against a panel of different tumor xenografted models. As the overexpression of P-gp pumps is generally related to resistance to tubulin binding agents, we have analyzed whether the expression of this efflux pump could also confer resistance to PM060184. In vitro, PM060184 showed potent antiproliferative activity against tumor cells over-expressing the P-gp multidrug efflux pump (LoVo/Dox, A2780/Dox and IGROV-1/ET), with IC50s values in the low nanomolar range. In vivo, the activity of PM060184 was evaluated in mice xenografted with LoVo (wild-type) or LoVo/DX (P-gp overexpressing) subcutaneous tumors. Tumor bearing (ca. 150-200 mm3) animals were randomly allocated into the following groups (N = 10/group): i) PM060184 (16 mg/kg); ii) paclitaxel (25 mg/kg); iii) vinorelbine (16 mg/kg); and, iv) placebo. Treatments were intravenously administered once per week for 3 consecutive weeks (q7dx3). Tumor dimensions were recorded 3 times per week starting from the first day of treatment (Day 0). Tumor volume was calculated using the equation (a·b2)/2, where a and b were the longest and shortest diameters, respectively. The antitumor effect obtained following paclitaxel, vinorelbine or PM060184 administration was calculated by using T/C (%), which was defined as the percentage of the change in tumor volume for each treated (T) and placebo (C) group during the surviving period for placebo-treated animals. In mice bearing LoVo xenografted tumors paclitaxel and vinorelbine treatments induced lowest T/C values of 23.3 % (Day 26) and 18.3% (Day 23), respectively. Also, PM060184 was highly active in this model, with a lowest T/C calculated as 8.1 % (Day 26). In LoVo/DX xenografted mice, paclitaxel and vinorelbine treatments resulted in no antitumor effect. However, LoVo/DX tumors were highly susceptible to PM060184 treatment (lowest T/C = 6.7%, on Day 28) demonstrating that a strong antitumor PM060184-related effect regardless of the P-gp status in this model. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A173. Citation Format: Pablo M. Aviles, Maria José Guillen, Mandy Palomares, Praxedes Nuñez, Marta Martinez-Diez, Juan Fernando Martínez-Leal, Luis Francisco García-Fernández, Carlos M. Galmarini. The new marine derived tubulin binding agent PM060184 shows potent antitumor activity in vivo against multidrug resistant, Pgp expressing tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A173.