Abstract 5386: Lenalidomide enhances the anti-prostate cancer activity of docetaxel <i>in vitro</i> and <i>in vivo</i>
Authors: Jake Y. Henry, Ling Lu, Mary Adams, Brendan Meyer, Blake Bartlett, Angus G. Dalgleish, Christine Galustian
Journal: Cancer Research (2010)

Abstract Introduction: Prostate cancer accounts for approximately a third of all cancers in men. The FDA has approved the use of docetaxel in combination with prednisone for the treatment of Castrate Resistant Prostate Cancer (CRPC). However, it commonly elicits toxic reactions at effective doses. Thus combination of docetaxel with agents exhibiting non-overlapping toxicities is required. Combined, docetaxel and thalidomide are effective in treating patients with metastatic CRPC. Lenalidomide (Revlimid®), a thalidomide analogue, is FDA approved for multiple myeloma (MM) in combination with dexamethasone and in del 5q myelodysplastic Syndrome (MDS). Phase I study results suggest that docetaxel and lenalidomide actively combine in HRPC and a phase III trial is underway. Lenalidomide is known to exert direct tumoricidal effects only against subsets of hematological tumors. However, there are multiple effects on signalling pathways related to cell survival and proliferation which may also affect solid tumor biology. Aims: We have evaluated direct single agent lenalidomide activity as well as potential synergistic effects of combining docetaxel and lenalidomide using in vitro and in vivo models of prostate cancer. Methods: The effect of lenalidomide alone (up to 1 microM) or in combination with docetaxel (0.32-200nM) was assessed on the proliferation of EGF-stimulated prostate cancer cells. In vitro transwell invasion assays were also performed to assess the ability of lenalidomide to inhibit EGF-induced PC3 and DU145 cell invasion. The effect of combining docetaxel and lenalidomide in an in vivo model of tumor growth was studied by injecting 5×106 PC3 cells into the flanks of nude mice. Mice were treated with docetaxel (8mg/kg, bi-weekly) and lenalidomide (50mg/kg, daily) until tumors reached 1400mm3. Results: Single agent lenalidomide did not significantly inhibit EGF-induced PC3 proliferation; however at 1 microM, lenalidomide reduced the IC50 of docetaxel by an average of 42%. Lenalidomide displayed potent single agent activity by completely inhibiting EGF-induced PC3 and DU145 cell invasion (p&amp;lt;0.001). In mice treated with a combination of lenalidomide and docetaxel, median survival increased to 59 days vs 48 days (lenalidomide alone) and 41 days (docetaxel alone) with a corresponding reduction (p&amp;lt;0.05) in tumor growth. Conclusions: These results demonstrate that lenalidomide alone displays direct effects against prostate cancer cells by inhibiting growth factor induced invasion. Lenalidomide enhances the anti-proliferative effect of docetaxel in vitro. Combinatorial activity was further confimed in a xenograft model showing that combination of lenalidomide and docetaxel produced a hyperadditive effect that slows tumor progression leading to enhanced median overall survival. These results support the use of lenalidomide in combination with docetaxel as an effective treatment for patients with CRPC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5386.