Abstract A43: Lenalidomide enhances the anti-proliferative activity of docetaxel in <i>in vivo</i> and <i>in vitro</i> models of prostate cancer
Authors: Jake Y. Henry, Ling Lu, Mary Adams, Brendan Meyer, Blake Bartlett, Angus G. Dalgleish
Journal: Clinical Cancer Research (2010)

Abstract Introduction: Prostate cancer is the most commonly diagnosed form of cancer in men in the United Sates, with the second highest rate of mortality. In 2004, the FDA 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 nonoverlapping toxicities may be an effective way of improving treatment options for patients. Docetaxel and thalidomide have been reported to show efficacy in the treatment of patients with metastatic CRPC. Lenalidomide (Revlimid®), a thalidomide analogue, is FDA approved for the treatment of previously treated multiple myeloma (MM) in combination with dexamethasone and in the del 5q subset of myelodysplastic syndromes (MDS). Reports from a phase I study suggest that docetaxel and lenalidomide is an active combination in CRPC and a phase III trial is now underway. Lenalidomide is known to exert immunomodulatory and anti-angiogenic effects but is generally considered to exert direct tumoricidal effects only against subsets of haematological tumor cells. However, there are reports of multiple effects on signalling pathways related to cell survival and proliferation, including TNF-α, IL-6, ERK, PI3K, VEGF, p27, and P21 which may also effect 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 µM) or in combination with docetaxel (0.32-200 nM) was assessed on the proliferation of EGF-stimulated prostate cancer cells. Annexin V and TUNEL assays were used to investigate the apoptotic effects of combining lenalidomide and docetaxel on 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 (8 mg/kg, biweekly) and lenalidomide (50 mg/kg, daily) until tumors reached 1400 mm3. Results: Single agent lenalidomide did not significantly inhibit EGF-induced PC3 proliferation; however at 1 µM (PC3) and 0.01 µM (DU145), lenalidomide reduced the IC50 of docetaxel by approximately 40%. These combinations increased apoptosis by upto 50% (p&amp;lt;0.05) in the cell lines as measured by Annexin V and TUNEL assays. 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 antiproliferative effects of docetaxel in vitro through an enhancement of apoptosis of prostate cancer cells. Combinatorial activity was further confirmed 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. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A43.