Sunitinib blocks tumoral growth on an orthotopic model of human testicular germ cell tumors

Abstract

16070 Background: Germ cell tumors (GCTs) of the testis are highly curable, but patients refractory to cisplatin (CDDP) based chemotherapy have a poor prognosis. Several studies support an important role of angiogenesis in GCT, suggesting anti-angiogenic treatment as a good alternative. Sunitinib is an oral multitarget tyrosine kinase receptor with antiangiogenic and antitumoral activities. We evaluate the effect of sunitinib, CDDP or the combination of both compounds on tumoral growth using an orthotopic model of human testicular GCTs (Piulats et al., AACR 2006; abstract 2760). Methods: Mice were implanted with 4 different tumors: a yolk sac without prior exposure to CDDP; a choriocarcinoma from a CDDP-resistant patient; and finally both a choriocarcinoma without prior exposure to CDDP and its CDDP refractory variant induced in mice by a continous CDDP exposure. Mice were treated with sunitinib (40 mg/kg, daily for 15 days), CDDP (2 mg/kg three times at 5-day interval) or combination of both. Animals were sacrificed once tumors in vehicle-treated mice affected the well being of the animals and tumors were analyzed. Results: We observed a significant block of tumoral volume, decreased circulating αFP and βHCG serum levels, and longer survival after sunitinib treatment for all GCTs analyzed. Tumor disappeared when mice were treated combining CDDP and sunitinib. Moreover, in the model of CDDP refractory induced choriocarcinoma, sunitinib clearly blocked tumoral growth. Sunitinib treatment inhibited VEGFR1,2 and 3, Flt-3 and PDGFRα, levels in absence of any effect on EGFR or PDGFRβ levels. Conclusions: Sunitinib may play a role in the treatment of CDDP-resistant patients that warrants further investigation. No significant financial relationships to disclose.