Poster Presentations

Session Title: LIVER TUMORS a) EXPERIMENTAL
Presentation Date: Apr 24, 2009

THE COMBINATION EVEROLIMUS (RAD001) PLUS SORAFENIB IS SUPERIOR TO SORAFENIB MONOTHERAPY IN THE TREATMENT OF HEPATOCELLULAR CARCINOMA

A.-C. Piguet¹, V. Radojevic¹, M. Afthinos¹, C. Hora¹, M. Ledermann¹, B. Saar², J.-F. Dufour^1
1Department of Clinical Pharmacology and Visceral Research, ²Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University of Bern, Bern, Switzerland

Background and aims: We reported that mTOR inhibition significantly reduced tumoral growth and improved survival in an experimental model of hepatocellular carcinoma (HCC) (J Hepatol, 2007). The SHARP study demonstrated that sorafenib, a multikinase inhibitor which blocks the VEGF and PDGF receptors and the RAF kinase prolongs the survival of HCC patients. We tested the combined effects of the mTOR inhibitor RAD001 and sorafenib in an experimental model of HCC.
Methods: Single 2mm³ cubes of subcutaneously grown Morris Hepatoma cells were implanted into livers of ACI rats. Six days later, rats were randomized to RAD001 (5mg/kg 2x/week p.o.), sorafenib (7.5mg/kg/day p.o.), combination of both, sorafenib for two weeks followed by RAD001 for 3 weeks, or vehicle (6 animals/group). Tumoral growth was measured by MRI. Phosphorylation of Erk1/2 and 4E-BP1 in tumoral tissue was determined at end of study by Western blotting and mRNA levels of VEGF by TaqMan. Antiangiogenic effects of RAD001 and sorafenib were assessed by rat aortic ring assay. Data are mean±SD.
Results: 35 days after implantation, tumor sizes were 1139mm³±238 for vehicle, 421mm³±84 for RAD001, 805mm³±317 for sorafenib, 511mm³±183 for sequential treatment and 282mm³±73 for combination (p≤0.05 vs vehicle). No differences in body weight at sacrifice were observed between treatment groups. RAD001 and combination treatments decreased phosphorylation of 4E-BP1 compared to vehicle or sorafenib groups. Phosphorylation of Erk1/2 was decreased by sorafenib, but increased by RAD001. Compared to vehicle, VEGF tumoral mRNA levels were decreased by 0.7±0.2 and 0.8±0.4 fold in case of RAD001 and sequential treatment, but increased by 1.4±0.6 and 1.4±0.2 fold with sorafenib and combination respectively. In the rat aortic ring assay, vessel number was reduced by 57%, 61% and 71% by sorafenib 100nM, RAD001 200nM and the combination, respectively, and by 85% when sorafenib was added sequentially prior to RAD001.
Conclusion: The antitumoral effect of sorafenib was significantly increased when combined with RAD001, in part possibly due to a potentiation of the antiangiogenic effect of sorafenib. Adding RAD001 to sorafenib did not result in more toxicity in this experimental model. These findings provide rationale for combining these drugs in the treatment of HCC.