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. 2007 Jun 26;134(1):51–57. doi: 10.1007/s00432-007-0247-4

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

O Guérin 1, P Formento 2, C Lo Nigro 3, P Hofman 1, J L Fischel 2, M C Etienne-Grimaldi 2, M Merlano 3, J M Ferrero 2, G Milano 2,✉
PMCID: PMC12161743  PMID: 17593391

Abstract

Purpose

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®).

Methods

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.).

Results

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.

Conclusion

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

Keywords: Prostate cancer, Cetuximab, Sunitinib, Docetaxel, Drug combinations, Animal model

Introduction

Numerous studies are under way to assess the role of chemotherapy for patients at various stages of prostate cancer (Canil and Tannock 2004). One of the current treatments of reference in hormone-refractory prostate cancer consists in chemotherapy with docetaxel (taxotere) combined with prednisone (Khan et al. 2003). A recent controlled study by Tannock et al. (2004) enhanced the importance of administering docetaxel in prostate cancer by showing that, as compared with patients treated by mitoxantrone, those receiving docetaxel had a 0.76 (P = 0.009) of hazard ratio for death . Future strategies aimed at improving management of advanced prostate cancer should examine the benefits of adding other agents to docetaxel.

Numerous molecular mechanisms are linked to the transition to hormone-refractory prostate cancer (Amler et al. 2000). The increased expression of HER signaling family of proteins seems to be one important factor (Craft et al. 1999; Di Lorenzo et al. 2002). We recently examined the growth inhibitory effects of the anti-EGFR drug erlotinib, docetaxel, and 5′DFUR (the main intermediary metabolite of capecitabine) in combination, on the androgen receptor-negative human prostate cancer cell lines PC3 and DU145 (Fischel et al. 2006). Marked synergistic cytotoxic effects were observed following the application of the double combination of erlotinib-5′DFUR for both cell lines and to a lesser extent with the triple combination. For PC3 cells all conditions resulted in synergistic interaction (Fischel et al. 2006).

Physiological and molecular evidence support a role for neo-angiogenesis during progression of advanced prostate cancer (Strohmeyer et al. 2004; Aalinkeel et al. 2004). Sunitinib malate (SU11248; SUTENT®) is an oral, multi-targeted tyrosine kinase inhibitor that selectively and potently inhibits class III and V split kinase domain receptor tyrosine kinases, including: vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), platelet-derived growth factor receptors (PDGFR-α and -β), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 receptor (FLT3), and glial cell-line derived neurotrophic factor receptor (rearranged during transfection; RET) (Abrams et al. 2003; O’Farrell et al. 2003a, b; Mendel et al. 2003). Sunitinib has demonstrated antiangiogenic and anti-tumor activities in various solid tumor xenograft models, including colon, renal, breast and lung cancers. In addition, sunitinib recently received approval from the US FDA and European Agency for the treatment of advanced renal cell carcinoma and for the treatment of gastrointestinal stromal tumors after disease progression or intolerance to imatinib mesylate therapy (SUTENT 2006). The aim of this study was to explore a rational therapeutic approach by combining docetaxel with an EGFR-targeting agent and with an anti-angiogenic agent. We thus evaluated the anti-tumor and molecular effects of sunitinib in combination with the anti-EGFR agent cetuximab and docetaxel in immunodeficient mice with PC3 androgen-independent prostate cancer growing as a xenograft.

Material and methods

Chemicals

Sunitinib was kindly provided by Pfizer. Docetaxel and cetuximab were marketed drugs and were provided by our institution pharmacy. Working solutions were prepared extemporaneously as follows: cetuximab (0.03 g/l) and docetaxel (1.5 g/l) were diluted in 0.9% NaCl and sunitinib (6 g/l) suspended in citrate buffer pH 3.5 according to manufacturer’s indications. For all drugs the concentrations were adjusted to include the daily dose in 0.2 ml of drug solution/suspension. Dulbecco’s modified Eagle’s medium (DMEM), penicillin, streptomycin and glutamine were purchased from Whittaker (Verviers, Belgium). Fetal bovine serum (FBS) was obtained from Dutscher (Brumath, France).

Cell lines

PC3, a human androgen-independent cancer cell line, was obtained from the CNRS UMR 6543–Nice.

The cell line was maintained as mono-layer cultures in DMEM supplemented with 10% FBS v/v, 2 mM glutamic acid, 50,000 units/l penicillin and 80 μM streptomycin in a humidified incubator (Sanyo, Japan) at 37°C in an atmosphere containing 8% CO2. Batches of 15 × 106 cells were frozen in FBS supplemented with 5% DMSO v/v in advance for injection into mice. Shortly before injection, cells were thawed and suspended in Ringer lactate.

Mice

Animal experiments were performed in accordance with the “Principles of laboratory animal care” (NIH publication no. 85–23, revised 1985) and the US Animal Welfare Act as amended, as well as with the regulations of the institutional ethic commission. Six-week-old male NMRI nude mice were purchased from Janvier laboratories (Le Genet sur Isle, France) and were given s.c. inoculation in the right flank of 3 × 106 cells dissolved in 100 μl of Ringer lactate (ten animals per treatment condition).

Tumors

Tumor length and width were measured weekly using a caliper. Tumor volume was calculated as π/6 × length × width2 until animal sacrifice. At that time, animals were killed by spinal cord dislocation and tumors were subsequently removed surgically; half of the tumor was directly frozen in liquid nitrogen for protein analysis and the other half fixed in para-formaldehyde overnight for immunohistochemistry analyses.

Treatments

Mice bearing well-established PC3 tumors (mean tumor volume/treatment group ∼250 mm3) were treated every week with vehicle alone (controls), sunitinib (40 mg/kg/day, 5 days/week during 3 weeks, 0.2 ml p.o.), cetuximab (0.2 mg/kg/day, 5 days/week during 3 weeks, 0.2 ml i.p.) and docetaxel (10 mg/kg, 1 day/week during 3 weeks, 0.2 ml i.p.). The doses of cetuximab, docetaxel and sunitinib were chosen according to preliminary experiments to ensure that each drug given alone exerts moderate effects on tumor growth.

Interaction between sunitinib and cetuximab, docetaxel or their combination was evaluated for tumor-growth inhibition.

The effects of the treatments were examined as previously described by Prewett et al. (2002). The effect on tumor growth was measured by taking the mean tumor volume on different given days for the different treatment groups: controls, treatment a, treatment b and treatment a + b. Fractional tumor volume (FTV) for each treatment group was calculated as the ratio between the mean tumor volumes of treated and untreated tumors. This was done for treatment a (FTVa), for treatment b (FTVb) and for treatment a + b (FTV a + b). The expected FTV for the « a + b » combination was defined as FTVa-observed × FTVb-observed. The ratio FTV a + b-expected/ FTV a + b-observed was the combination ratio (CR). With the three drug abc combination, CR was defined alike with expected FTV (a + b + c) being FTVa × FTVb × FTVc and CR being the ratio expected FTV (a + b + c)/observed FTV (a + b + c). If CR > 1, there are supra-additive effects and if CR < 1 infra-additive ones. Strictly additive effects are observed if CR = 1.

Preparation of samples and analysis of cellular factors

Tumors were collected at the end of the observation period on day 84 when mean tumor volume of the controls reached 2,500 mm3 (dictated by ethical reasons).

Frozen tumors were pulverized in a liquid nitrogen-cooled Thermovac pulverizer. The resulting powders were homogenized in 10 vol. of a 10-mM Tris–HCl buffer pH 7.4, containing 1 mM EDTA, 0.5 mM dithiotreitol and 10 mM sodium molybdate. The homogenates were centrifuged for 1 h at 105,000g (+ 4°C) and the supernatants (cytosols) were used for protein determination by immuno-blotting. Total protein content was measured using the bicinchoninic acid assay.

The effects of each single drug and their combination were examined for the impact on tumor growth and tumor angiogenesis [von Willebrandt Factor (vWF)] and on molecular factors representative of EGFR signaling (phospho-ERK, 1/2), of apoptosis (caspase 3), and of proliferation (Ki67).

The micro-vessel marker vWF and the proliferation marker Ki67 expressions were determined in micro-tissue-arrays by immunohistochemistry using DAKO polyclonal antibody ref: A0082 for vWF and DAKO monoclonal antibody JC70A ref: M0823 for Ki67. The final score was the result of the examination of three fields per tumor, and between four and eight tumors were investigated. Labeling intensities were scored as 1 = slight, 2 = medium and 3 = strong.

The apoptosis-related marker caspase 3 was determined by Western blot using mouse monoclonal antibody CASPASE3/CCP32 from BD transduction laboratory.

The effects on vWF and Ki67 were evaluated using the non-parametric ANOVA (Kruskal–Wallis test). The differences between treatment groups for molecular factors (phospho-ERK, caspase 3 cleavage) were examined using the Mann–Whitney test.

Measurement of gene expression levels (PDGFRβ, KDR, EGFR, ABCB1)

The experiments were performed on PC3 growing in vitro (3 days after plating 4 × 105 cells in 25 cm2 flask, drugs were added for 24 h before RNA isolation) at a sunitinib concentration of 50 nM, which is in the range of the sunitinib IC50s for the inhibition of proliferation for PDGFRα (40 nM) and PDGFRβ (70 nM) or necessary to induce apoptosis (100 nM). The docetaxel concentration (100 nM) was in the range of the mean concentration for patients receiving docetaxel at 175 mg/m2. Individual drug concentrations were the same in the single drug and combination studies.

Total RNA was isolated using the Quiagen RNA isolation kit (Quiagen, Courtaboeuf, France) and the two-step GeneAmp RT-PCR kit (Applied Biosystem, Courtaboeuf, France) was used for RT-PCR, in accordance with the manufacturer’s protocol. For real-time RT-PCR, triplicates of 25 μl PCR reactions were performed on 2 μl of cDNA obtained by retro-transcription of 2 μg of RNA in a 100-μl reaction. Amplification and analysis were performed, following the manufacturer’s instructions, using the ABI PRISM 7000 Sequence Detection System (Applied Biosystems, Courtaboeuf, France) and the following assay on demand (Applera, https://products.appliedbiosystems.com/): ABCB1 (MDR1), EGFR (ERB1), VEGFR2 (KDR), PDGFRβ and Kit. Data were analyzed using the comparative Ct (Cycle threshold) method and were normalized to the Eukaryotic 18S rRNA as endogenous control. Gene expression was not considered to have been modified (under- or over-expressed, respectively) for values within the 0.5–2.0 range. Experiments were done in triplicate.

Results

Effects of sunitinib, cetuximab and docetaxel on tumor growth

Each drug, administered as a single-agent, demonstrated comparable and moderate effects on tumor growth with 64, 50 and 41% inhibition at the end of drug exposure for cetuximab, sunitinib and docetaxel, respectively. However, this was followed by rapid parallel re-growth with no statistically significant difference between control and treated tumor volumes at the end of the observation period (day 84), 30 days after the end of drug exposure (Fig. 1a).

Fig. 1.

Fig. 1

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a Growth inhibitory effects of sunitinib, cetuximab and docetaxel given alone on tumor. Bars = SD. b Growth inhibitory effects of sunitinib–docetaxel, sunitinib–cetuximab and sunitinib–docetaxel–cetuximab combinations on tumor. Bars = SD

Combinations of sunitinib–docetaxel, sunitinib–cetuximab and sunitinib–cetuximab–docetaxel (Fig. 1b) produced strong tumor growth inhibition after 1 week of treatment, which continued for 6–12 days after discontinuation of treatment (P = 0.03, P = 0.05 and P = 0.005 vs. control, respectively, at day 75) followed by tumor re-growth. However, in contrast with the effects of single drugs, the differences in tumor growth between control and sunitinib–docetaxel and sunitinib–docetaxel–cetuximab treated tumors were still statistically significant at the end of the observation period (P = 0.0096 and P = 0.0258 vs. control, respectively, at day 84).

The greatest reduction in tumor volume was observed in mice that had received combined sunitinib–docetaxel or sunitinib–cetuximab–docetaxel treatments.

Computed CR values determined on days 61, 68 and 75 after cell implantation indicate supra-additive effects for sunitinib–docetaxel (1.53, 1.15 and 1.47, respectively) and sunitinib–cetuximab combinations (1.2, 1.32 and 1.14, respectively), and suggest additive effects only for the sunitinib–cetuximab–docetaxel combination (CR = 1).

Stable mean mouse weight suggested that no drug-induced toxicity was evident (Fig. 2).

Fig. 2.

Fig. 2

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Evolution of the mean mice weight for different treatment groups during the observation period. Bars = SD

Molecular parameters

Evaluation of Ki67 and vWF expression (Figs. 3, 4, respectively) indicated that the differences in tumor growth between the tested experimental conditions were accompanied by a parallel diminution in both tumor cell proliferation and vascularization, respectively. It is noteworthy that, for these two parameters, the greatest reduction was demonstrated by the sunitinib–cetuximab–docetaxel triple-combination therapy.

Fig. 3.

Fig. 3

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Effect of the different treatments on the proliferation-related marker Ki67. The final score was the result of the examination of three fields per tumor, and between four and eight tumors were investigated. Labeling intensities are shown as 1 = slight, 2 = medium and 3 = strong, with the sum of all values in one histogram being 100%. Scoring was performed at the end of experiments on day 84

Fig. 4.

Fig. 4

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Effect of the different treatments on the endothelial cell marker vWF The final score was the result of the examination of three fields per tumor, and between four and eight tumors were investigated. Labeling intensities are shown as 1 = slight, 2 = medium, 3 = strong, with the sum of all values in one histogram being 100%. Scoring was performed at the end of experiments on day 84

There was no difference observed between single drug effects and control for the induction of apoptosis (caspase 3 cleavage, Fig. 5) in PC3 tumors. Likewise, the combination of sunitinib and cetuximab did not significantly modulate the cleaved caspase 3/caspase 3 ratio. In contrast, there were significantly more pro-apoptotic effects for the sunitinib–docetaxel containing combinations (i.e., sunitinib–docetaxel plus sunitinib–docetaxel–cetuximab) as compared to all other pooled conditions (P = 0.0395).

Fig. 5.

Fig. 5

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Effect of the different treatments on the apoptosis-related marker cleaved-caspase 3/caspase 3 ratio in PC-3 tumor xenografts. Western blot is a representative example of one of at least three experiments. Bars = SD

Effects of drugs on the expression of targets and modulators on PC3 cells growing in vitro

For both KDR and PDGFR (targets of sunitinib), there was no clear effect of 100 nM docetaxel on gene expression (c-KIT was not found to be expressed in PC3 cells). There was also no significant impact of sunitinib on MDR-1 (ABCB1) expression (potential modulator of docetaxel activity). Of note, when examining the docetaxel–sunitinib association, there were changes in EGFR and ABCB1 gene expression levels with a moderate increase for EGFR and a more marked one for ABCB1 (Table 1).

Table 1.

Changes in gene expression in PC3 growing in vitro in the presence of single drugs and docetaxel–sunitinib combination

Docetaxel 100 nM Sunitinib 50 nM Combination Statistical analysis
PDGFRβ 1.2 ± 0.2 1 ± 0.2 1.5 ± 0.2 ns
EGFR 0.8 ± 0.25 0.8 ± 0.4 2.7 ± 2 ns
KDR 0.5 ± 0.4 0.9 ± 0.5 1.7 ± 0.7 P = 0.088
ABCB1 (MDR-1) 0.7 ± 0.3 0.7 ± 0.3 10.8 ± 8.8 P = 0.08
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Values have been normalized, with 1 being the gene expression level for the control without drugs

ANOVA for the statistical analysis comparing the three conditions

Discussion

The introduction of docetaxel into clinical practice has opened up a new era of improvement in the management of advanced hormone-refractory prostate cancer (Tannock et al. 2004; Petrylak 2005; Engels et al. 2005). Febbo et al. (2005) have recently reported on neo-adjuvant use of docexatel before radical prostatectomy in prostate cancer patients with high-risk localized lesions. They observed that the treatment was well tolerated and often resulted in a PSA decline of more than 50% concomitant with significant tumor volume reduction (Febbo et al. 2005). As recently outlined by Engels et al. (2005), current research into docetaxel-based chemotherapy should include drug combinations in order to combine improved outcome with acceptable feasibility.

Membrane receptors of the HER family are associated with the hormone-independence of prostate cancer (Craft et al. 1999). A recent experimental study by Festuccia et al. (2005) suggested that blockade of the EGFR pathway itself can attenuate the invasive potential of PCa cells. Clinical results arising from phase I studies targeting EGFR in advanced prostate cancer were encouraging (Lorusso 2003). However, a recent phase II study of the EGFR tyrosine kinase inhibitor gefitinib, showed relatively disappointing clinical results as single agent therapy (Canil et al. 2005). Significant therapeutic results in experimental models of human prostate cancer in nude mice have been reported with combinations of taxanes and tyrosine kinase inhibitors directed against EGFR (Kim et al. 2003, 2004). Thus, combining taxanes and EGFR inhibitors should provide more promising clinical results than EGFR-targeting alone in advanced hormone-refractory prostate cancer. Recent experimental data support the idea that decreasing angiogenesis may be a rational therapeutic approach for treatment of hormone-resistant prostate cancer (Kim et al. 2004; Perryman et al. 2006; Su et al. 2006). This background inspired the present experimental study aimed at examining the anti-tumor effect resulting from a triple combination of docetaxel, sunitinib and cetuximab applied to a representative hormone-refractory human prostate cancer cell line PC3 growing as a xenograft in immune-deficient mice.

One of the main results of the present study is that the greatest reduction in tumor growth was obtained with the triple association. Interestingly, stable mean weight of treated animals indicated an absence of major drug-induced toxicity. In addition, the combination of the three selected agents led to the greatest degree of induction of the apoptotic pathway (caspase 3 cleavage, Fig. 5). Immunohistochemical analyses also indicated that the triple association led to a sustained diminution of tumor proliferation (Ki67, Fig. 3) and also, interestingly, to a marked reduction of tumor endothelial cell labeling (VWF expression, Fig. 4). This means that the triple combination impacted both the tumor itself and its endothelial environment, thus probably explaining the anti-tumor effects. Others (Tonra et al. 2006) and ourselves (Bozec et al. 2006), have recently published on the anti-tumor synergistic effects observed when combining EGFR-targeting with anti-angiogenic treatments. The present study confirms these data with a supra-additive anti-tumor effect resulting from the sunitinib–cetuximab combination compared with either single agent alone. Of note, the present data indicate that the major component contributing to the anti-tumor efficacy of the triple combination results mainly from the association between the anti-angiogenic agent sunitinib and the cytotoxic drug docetaxel. This conclusion is supported by the tumor growth curves (Fig. 1b) in which the inhibitory effects on tumor growth produced by docetaxel–sunitinib are very similar to those resulting from the triple association. This observation is corroborated by CR calculations with the value of 1.0 for the triplet combination indicating additivity and value above 1.0 for the docetaxel–sunitinib doublet combination indicating supra-additivity. In addition, the molecular impact of the triple association was very close to that already obtained with the docetaxel-sunitinib combination, as seen with caspase 3 cleavage, Ki67 expression and anti-angiogenic effects through vWF labeling. The present results with this dual combination of sunitinib and docetaxel concur well with the recent data reported by Kim et al. (2006). These authors applied imatinib, a PDGFR inhibitor, combined with paclitaxel to multidrug-resistant human PC3 cells implanted in immunodeficient mice (bone metastasis model). They found that the combined treatment had a major impact on tumor-associated endothelial cells. In addition, it has recently been reported that a combined regimen of sunitinib with the cytotoxic drug cyclophosphamide led to substantive reductions in tumor xenografts (Pietras and Hanahan 2005). Our data concur well with the latter data. It is now clinically established that anti-angiogenic treatments could be favorably combined with chemotherapeutic drugs, as shown for the avastin–fluorouracil–irinotecan association in advanced colorectal cancer (Hurwitz et al. 2004). A synergistic interaction between an anti-angiogenic agent and a chemotherapeutic agent is somewhat counterintuitive since the inhibition of tumor angiogenesis may decrease delivery of drugs and, therefore, antagonize chemotherapy. The notion of transient “normalization” of the abnormal structure and function of tumor vasculature by anti-angiogenic agents is one of the hypotheses, which reconcile the theoretical view and the reality of the results when combining anti-angiogenic agents and chemotherapeutic drugs (Jain 2001). It was not in the scope of the present study to examine this hypothesis. The possible impacts of single drugs on the molecular determinants of the associated drug were examined. Docetaxel had no effect on either KDR or PDGFR-β expression. As sunitinib did not modify the expression of MDR-1 (ABCB1), a gene, which can modulate the activity of docetaxel, the supra-additive interaction between sunitinib and docetaxel, could not be explained by a modulation of MDR-1. On the contrary there was a tendency for an increase in MDR-1 expression under the presence of the two drugs. This finding could be more deeply explored in the perspective of a repeated treatment with successive docetaxel-sunitinib sequences. Also, the association docetaxel-sunitinib increased EGFR expression, a molecular event, which could be in favor of the association with cetuximab. This latter observation could argue in favor of an application of cetuximab following the docetaxel–sunitinib exposure.

Summing up, the supra-additive anti-tumor effect observed with the combination of sunitinib–docetaxel might support innovative strategies for the management of advanced prostate cancer.

Acknowledgment

PFIZER France is acknowledged for the financial support of this work.

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