Supra-additive antitumor effect of sunitinib malate (SU11248, Sutent^®) combined with docetaxel. A new therapeutic perspective in hormone refractory prostate cancer

Physiological and molecular findings indicate over-expression of HER proteins and dysregulation of neo-angiogenesis during progression of advanced prostate cancer. The aim of this study was to test a novel rational therapeutic approach by combining docetaxel with an EGFR-targeting agent (cetuximab) and with an anti-angiogenic agent (sunitinib, SUTENT^®).

Mice bearing well-established PC3 prostate tumors (mean tumor volume/treatment group ∼250 mm³) were treated every week with vehicle alone (controls), sunitinib (40 mg/kg/day, 5 days/week for 3 weeks, 0.2 ml p.o.), cetuximab (0.2 mg/kg/day, 5 days/week for 3 weeks, 0.2 ml i.p.) and docetaxel (10 mg/kg, 1 day/week for 3 weeks, 0.2 ml i.p.).

Each drug, administered as a single-agent, demonstrated comparable and moderate effects on tumor growth with approximately 50 % inhibition at the end of the 3-week dosing schedule. Computed combination ratio (CR) values for tumor growth determined on days 61, 68 and 75 after cell implantation indicated supra-additive effects for the sunitinib-docetaxel (1.53, 1.15 and 1.47, respectively) and sunitinib–cetuximab combinations (1.2, 1.32 and 1.14, respectively), and suggested additive effects only for the sunitinib–cetuximab–docetaxel combination (CR = 1). The effects on tumor growth were accompanied by a parallel diminution in tumor cell proliferation (Ki 67) and tumor vascularization (von Willebrandt factor). There were significantly higher pro-apoptotic effects (caspase-3 cleavage) observed for the sunitinib–docetaxel and sunitinib–docetaxel–cetuximab as compared to the other conditions.

The supra-additive anti-tumor effect observed with the sunitinib–docetaxel combination might support innovative strategies in the management of advanced prostate cancer.