Blake Bartlett

Recent Pharmacological Advances: Focus on Small-cell Lung Cancer

Small cell lung cancer (SCLC) represents approximately 15% of all lung cancers, and is the most aggressive form of lung cancer. Left untreated, the time from diagnosis to death is 2–3 months. With current treatment, expected survival is 7–20 months, depending on the stage of disease. A new drug, amrubicin, is approved in Japan for lung cancer and has demonstrated efficacy in U.S. and European phase II trials of SCLC patients with either untreated disease or relapsed refractory illness. In a phase II study of amrubicin in previously untreated patients, response rates reached 75% with a median survival time of almost 1 year. Amrubicin is a fully synthetic 9-aminoanthracycline, and an analog of doxorubicin and epirubicin. The major mechanism of action of amrubicin is inhibition of topoisomerase II. Unlike doxorubicin, however, it exhibits little or no cardiotoxicity in clinical studies and preclinical models. In preclinical rodent tumor models, it is selectively distributed to tumour tissue and is not detected in the heart when compared with doxorubicin, which is distributed equivalently to these sites. The primary metabolite of amrubicin, amrubicinol, is up to 100 times more cytotoxic in vitro than the parent compound. This review describes the mechanisms of action of amrubicin as well as clinical studies which demonstrate the potential of this drug in future SCLC treatment. The review also puts forward hypothetical considerations for the use of other drugs such as lenalidomide, an immunomodulatory drug acting on multiple signalling pathways, or histone deacetylase inhibitors, in combination with amrubicin in SCLC.

Abstract A43: Lenalidomide enhances the anti-proliferative activity of docetaxel in in vivo and in vitro models of prostate cancer

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 5×10 6 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 mm 3 . 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 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.

Abstract 5386: Lenalidomide enhances the anti-prostate cancer activity of docetaxel in vitro and in vivo

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC 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<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<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.