Lurbinectedin delays the onset of splenomegaly and extends survival of C26 tumor-bearing mice

Lurbinectedin (PM01183, PM) is a synthetic alkaloid derivate of trabectedin (ET743, ET), a marine-derived anticancer agent. PM is a DNA minor groove covalent binder that has been tested in different Phase I-III trials. It affects tumor microenvironment by limiting the production of inflammatory cytokines. Some of these cytokines are elevated in various cancers characterized by rapid body wasting with muscle, fat and cardiac tissue depletion (i.e. cachexia). Differing from ET, PM displays less liver toxicity, and less endothelial inflammation at the site of injection. Mice injected with murine colon adenocarcinoma C26 cells display cachexia, increased circulating levels of inflammatory cytokines, acute phase response activation and subsequent splenomegaly. Thus, we tested whether PM, at doses with no antitumoral activity on C26 colon adenocarcinoma, has any beneficial effects in mice against C26-induced cachexia. 10-weeks old BALB/c mice were injected subcutaneously with C26 cells and three days later randomized to receive into their tail vein, three times a week for three weeks 0.07 mg/kg PM (n = 8) or vehicle (n = 8). C26-carrying mice showed decreased body weights and premature death. Strikingly, PM was able to extend the lifespan of C26-bearing mice by about 85% from a median survival time of 20 days (range day 10-31) to a median survival time of 37 (range day 14-41). This occurred without affecting tumor growth or food intake or the number of lung metastases. Another set of mice were sacrificed at 10-13 days from C26 implant. PM did not grossly protect multiple tissues (fat, muscle, heart) from cachexia. Preliminary data showed that C26-induced splenomegaly was inhibited by PM administration as long as PM treatment lasted. In C26-bearing mice, this effect exerted by PM seems to be associated also to restrained circulating levels of M-CSF, but not of other inflammatory cytokines (i.e. IL-6, G-CSF or GM-CSF). Further studied are necessary to correlate the improved survival with the pharmacodynamic effect observed.