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

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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.

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References

  • Aalinkeel R, Nair MP, Sufrin G, et al (2004) Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res 64:5311–5321

    Article  PubMed  CAS  Google Scholar 

  • Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2:471–478

    PubMed  CAS  Google Scholar 

  • Amler LC, Agus DB, LeDuc C, et al (2000) Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res 60:6134–6141

    PubMed  CAS  Google Scholar 

  • Bozec A, Lassalle S, Gugenheim J, et al (2006) Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126. Br J Cancer 95:722–728

    Article  PubMed  CAS  Google Scholar 

  • Canil CM, Tannock IF (2004) Is there a role for chemotherapy in prostate cancer? Br J Cancer 91:1005–1011

    PubMed  CAS  Google Scholar 

  • Canil CM, Moore MJ, Winquist E, et al (2005) Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol 23:455–460

    Article  PubMed  CAS  Google Scholar 

  • Craft N, Shostak Y, Carey M, Sawyers CL (1999) A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5:280–285

    Article  PubMed  CAS  Google Scholar 

  • Di Lorenzo G, Tortora G, D’Armiento FP, et al (2002) Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res 8:3438–3444

    PubMed  CAS  Google Scholar 

  • Engels FK, Sparreboom A, Mathot RA, Verweij J (2005) Potential for improvement of docetaxel-based chemotherapy: a pharmacological review. Br J Cancer 93:173–177

    Article  PubMed  CAS  Google Scholar 

  • Febbo PG, Richie JP, George DJ, et al (2005) Neoadjuvant docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer. Clin Cancer Res 11:5233–5240

    Article  PubMed  CAS  Google Scholar 

  • Festuccia C, Angelucci A, Gravina GL, et al (2005) Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity. EGF-receptor inhibition may prevent tumor cell dissemination. Thromb Haemost 93:964–975

    PubMed  CAS  Google Scholar 

  • Fischel JL, Ciccolini J, Formento P, Ferrero JM, Milano G (2006) Synergistic cytotoxic interaction in hormone refractory prostate cancer with the triple combination docetaxel-erlotinib and 5′DFUR. Experimental data. AntiCancer Drugs 17:807–813

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  PubMed  CAS  Google Scholar 

  • Khan MA, Carducci MA, Partin AW (2003) The evolving role of docetaxel in the management of androgen-independent prostate cancer. J Urol 170:1709–1716

    Article  PubMed  CAS  Google Scholar 

  • Kim SJ, Uehara H, Karashima T, Shepherd DL, Killion JJ, Fidler IJ (2003) Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice. Clin Cancer Res 9:1200–1210

    PubMed  CAS  Google Scholar 

  • Kim SJ, Uehara H, Yazici S, et al (2004) Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice. Cancer Res 64:4201–4208

    Article  PubMed  CAS  Google Scholar 

  • Kim SJ, Uehara H, Yazici S, et al (2006) Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate cancer. J Natl Cancer Inst 98:783–793

    Article  PubMed  CAS  Google Scholar 

  • Lorusso PM (2003) Phase I studies of ZD1839 in patients with common solid tumors. Semin Oncol 30:21–29

    Article  PubMed  CAS  Google Scholar 

  • Mendel DB, Laird AD, Xin X, et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337

    PubMed  CAS  Google Scholar 

  • O’Farrell AM, Abrams TJ, Yuen HA, et al (2003a) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605

    Article  PubMed  CAS  Google Scholar 

  • O’Farrell AM, Foran JM, Fiedler W, et al (2003b) An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 9:5465–5476

    PubMed  CAS  Google Scholar 

  • Perryman LA, Blair JM, Kingsley EA, et al (2006) Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo. Biochem Biophys Res Commun 345:1207–1214

    Article  PubMed  CAS  Google Scholar 

  • Petrylak DP (2005) Future directions in the treatment of androgen-independent prostate cancer. Urology 65:8–12

    Article  PubMed  Google Scholar 

  • Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952

    Article  PubMed  CAS  Google Scholar 

  • Prewett MC, Hooper AT, Bassi R, et al (2002) Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8:994–1003

    PubMed  CAS  Google Scholar 

  • Strohmeyer D, Strauss F, Rossing C, et al (2004) Expression of bFGF, VEGF and c-met and their correlation with microvessel density and progression in prostate carcinoma. Anticancer Res 24:1797–1804

    PubMed  CAS  Google Scholar 

  • Su B, Zheng Q, Vaughan MM, Bu Y, Gelman IH (2006) SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition. Cancer Res 66:5599–5607

    Article  PubMed  CAS  Google Scholar 

  • SUTENT (sunitinib malate) (2006) Prescribing information. Pfizer Inc, New York

    Google Scholar 

  • Tannock IF, de Wit R, Berry WR, et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–12

    Article  PubMed  CAS  Google Scholar 

  • Tonra JR, Deevi DS, Corcoran E, et al (2006) Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res 12:2197–207

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

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

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Authors and Affiliations

  1. Nice General Hospital, Nice, France

    O. Guérin & P. Hofman

  2. Oncopharmacology Unit, Centre Antoine Lacassagne, 33, Avenue de Valombrose, 06189, Nice Cedex 2, France

    P. Formento, J. L. Fischel, M. C. Etienne-Grimaldi, J. M. Ferrero & G. Milano

  3. Laboratorio Oncologia Translazionale, ASO S. Croce e Carle, Cuneo, Italy

    C. Lo Nigro & M. Merlano

Authors
  1. O. Guérin
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  2. P. Formento
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  3. C. Lo Nigro
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  4. P. Hofman
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  5. J. L. Fischel
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  6. M. C. Etienne-Grimaldi
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  7. M. Merlano
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  8. J. M. Ferrero
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  9. G. Milano
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Corresponding author

Correspondence to G. Milano.

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Guérin, O., Formento, P., Lo Nigro, C. et al. Supra-additive antitumor effect of sunitinib malate (SU11248, Sutent®) combined with docetaxel. A new therapeutic perspective in hormone refractory prostate cancer. J Cancer Res Clin Oncol 134, 51–57 (2008). https://doi.org/10.1007/s00432-007-0247-4

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  • DOI: https://doi.org/10.1007/s00432-007-0247-4

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