Abstract C206: High antitumor complete response rate to Namitecan (ST1968) in preclinical model of pediatric sarcomas.
Authors: Pisano Claudio , Cassinelli Giuliana , Zuco Valentina , Petrangolini Giovanna , De Cesare Michelandrea , Tortoreto Monica , Lanzi Cinzia , Orlandi Augusto , Passeri Daniela , Meco Daniela , Di Francesco Angela Maria , Riccardi Riccardo , Bucci Federica , Zunino Franco 
Published: June 2012

Namitecan (ST1968), a new water-soluble camptothecin analogues, exhibits an improved pharmacological profile over conventional camptothecins. This molecule was selected for clinical development on the basis of preclinical evidence of superior efficacy than Topotecan or irinotecan and of its favorable therapeutic index. Namitecan has shown an high rate of sustained disease control in patients with solid tumors in Phase I, as predicted by preclinical data. Given the interest for the irinotecan treatment of pediatric tumors, this study was designed to explore the efficacy of Namitecan in preclinical models of pediatric sarcomas (TC-71, RH30, RD/TE671, A204 and U2OS cell lines). Namitecan showed an impressive antitumor efficacy in 4/5 of the tested xenograft sarcoma models at doses ranging 15–30 mg/kg given i.v. in a q4d×3w, as documented by the rate of complete tumor regression without evidence of tumor regrowth at the end of the experiments (around 120 days).

The outstanding Namitecan activity against pediatric sarcoma xenografts is emphasized by the observation that complete tumor regression could be achieved also by the dose of 15 mg/kg (i.e., ½ MTD) allowing the use of well-tolerated effective doses in clinical therapy. Moreover, the i.v. administration of Namitecan resulted in a high and persistent drug accumulation in TC-71 tumor xenograft, which could account for the good therapeutic index.

Since no correlation could be found between in vitro growth inhibitory activity and in vivo antitumor efficacy, it is likely that other in vivo effects may contribute to the drug antitumor efficacy. Indeed, in the RD/TE671 rhabdomyosarcoma model, we found that Namitecan activity was associated with a marked antiangiogenic effect, which was consistent with the down regulation of proangiogenic factors, including VEGF, bFGF and CCL-2, an angiogenesis chemokine mediator. Furthermore, we found that HIF-1α expression is strongly down regulated in our cellular models following treatment with Namitecan. These findings are in line with a supposed antiangiogenic activity of camptothecins likely to affect proliferation and migration of endothelial cells and down regulation of angiogenic factors and the known ability of Topoisomerase I inhibitors to inhibit the translation of HIF-1α protein which is a transcriptional activator of VEGF.

In conclusion, the available evidence supports that inhibition of angiogenesis contributes to the responsiveness of pediatric sarcomas to Namitecan, according to the role of angiogenesis in malignant behavior of these tumor types. Thus, the impressive efficacy of Namitecan against pediatric sarcoma may reflect: i) direct cytotoxic effects on tumor cells, as a result of persistent tumor accumulation of the drug and high topo I expression, ii) inhibition of angiogenesis and iii) a favorable in vivo drug distribution.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C206.