Key Points
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Vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and stem-cell growth factor receptor (KIT) are tyrosine kinases that have a major role in tumour cell proliferation and angiogenesis.
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Sunitinib (Sutent; Pfizer), a novel oral multitargeted tyrosine kinase receptor inhibitor blocks the activation of VEGFRs 1–3, PDGFRα, PDGFRβ, KIT, fms-related tyrosine kinase 3 (FLT3), RET and colony-stimulating factor receptor 1 (CSF1R), resulting in anti-angiogenic and antitumor activity against a broad range of malignancies.
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Sunitinib has been registered as a first-line therapy in patients with advanced renal cell carcinoma, as well as in imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumours (GISTs).
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Sunitinib may be used at the dose of 50 mg per day on an intermittent 4-week on/2-week off schedule, or continuously at the dose of 37.5 mg per day with a safe toxicity profile.
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In addition to tumour shrinkage that can be easily evaluated according to RECIST criteria, changes in tumour density may reflect sunitinib antitumor activity, requiring additional imaging criteria.
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Promising results have been reported in other tumour types including hepatocellular carcinoma and neuroendocrine tumours.
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Resistance to sunitinib may require mutations of tyrosine kinase as demonstrated for KIT in GIST, as well as evasion of VEGF/VEGFR-dependent signalling pathways in tumour or endothelial cells.
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Combinations with other targeted therapy and/or chemotherapy may broaden the spectrum of activity and/or circumvent resistance to sunitinib.
Abstract
Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors.
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References
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Folkman, J. What is the evidence that tumors are angiogenesis dependent? J. Natl Cancer Inst. 82, 4–6 (1990).
Cherrington, J. M., Strawn, L. M. & Shawver, L. K. New paradigms for the treatment of cancer: the role of anti-angiogenesis agents. Adv. Cancer Res. 79, 1–38 (2000).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Faivre, S., Djelloul, S. & Raymond, E. New paradigms in anticancer therapy: targeting multiple signalling pathways with kinase inhibitors. Semin. Oncol. 33, 407–420 (2006).
Motzer, R. J. et al. Sunitinib versus interferon α in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007). A pivotal study demonstrating the superiority of sunitinib over the previous standard of care in advanced RCC, for example IFNα.
Demetri, G. D. et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomized controlled trial. Lancet 368, 1329–1338 (2006). A pivotal study demonstrating the antitumour activity of sunitinib in patients with GIST resistant to imatinib, a situation that had no previous standard treatment.
Humar R., Kiefer, F. N., Berns, H. & Battegay, E. J. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR-)dependent signaling. FASEB J. 16, 771–780 (2002).
Lewis, C. & Murdoch, C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am. J. Pathol. 167, 627–635 (2005).
Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nature Med. 8, 841–849 (2002).
Rehman, J., Li, J., Orschell, C. M. & March, K. L. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 107, 1164–1169 (2003).
Ribatti, D. The involvement of endothelial progenitor cells in tumor angiogenesis. J. Cell. Mol. Med. 8, 294–300 (2004).
Hida, K. et al. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 64, 8249–8255 (2004).
Hicklin, D. J. & Ellis, L. M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 23, 1–17 (2005).
Erber, R. et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 18, 338–340 (2004).
Cao, Y. Emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nature Rev. Cancer 5, 735–743 (2005).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion and metastasis. Cell 124, 263–266 (2006). This recent review points out the crucial role of macrophages for tumour cell migration and initiation of angiogenesis.
Adini, A., Kornaga, T., Firoozbakht, F. & Benjamin, L. E. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res. 62, 2749–2752 (2002).
Grimshaw, M. J., Naylor, S. & Balkwill, F. R. Endothelin-2 is a hypoxia-induced autocrine survival factor for breast tumor cells. Mol. Cancer Ther. 1, 1273–1281 (2002).
Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nature Rev. Cancer. 3, 401–410 (2003).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
Mendel, D. B. et al. 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 (2003).
Sun, L. et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 46, 1116–1119 (2003).
Osusky, K. L. et al. The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels. Angiogenesis 7, 225–233 (2004).
Duensing, A., Heinrich, M. C., Fletcher, C. D. & Fletcher, J. A. Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest. 22, 106–116 (2004).
Naoe, T. & Kiyoi, H. Normal and oncogenic FLT3. Cell. Mol. Life Sci. 61, 2932–2938 (2004).
Ichihara, M., Murakumo, Y. & Takahashi, M. RET and neuroendocrine tumors. Cancer Lett. 204, 197–211 (2004).
Sapi, E. The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update. Exp. Biol. Med. 229, 1–11 (2004).
Baratte, S. et al. Quantitation of SU11248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J. Chromatogr. A 1024, 87–94 (2004).
Abrams, T. J. et al. SU11248 inhibits KIT and platelet-derived growth factor receptor β in preclinical models of human small cell lung cancer. Mol. Cancer Ther. 2, 471–478 (2003).
Murray, L. J. et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin. Exp. Metastasis 20, 757–766 (2003).
O'Farrell, A. M. et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101, 3597–3605 (2003).
Faivre, S. et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J. Clin. Oncol. 24, 25–35 (2006). A report on the first in man experience (Phase I trial) using sunitinib in patients with advanced cancers; identifies tumour types that benefited from sunitinib including RCC, imatinib-resistant GIST and NETs.
Motzer, R. J., Hoosen, S., Bello, C. L. & Christensen, J. G. Sunitinib malate for the treatment of solid tumors: a review of current clinical data. Expert Opin. Investig. Drugs 15, 553–561 (2006).
Motzer, R. J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).
Motzer, R. J. et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295, 2516–2524 (2006).
Motzer R. J. et al. Sunitinib versus interferon-α (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC): updated results and analysis of prognostic factors. J. Clin. Oncol. 25 (Suppl. 18), 5024 (2007).
Judson, I. R., et al. Updated results from a Phase III trial of sunitinib in advanced gastrointestinal stromal tumor (GIST). Ann. Oncol. 17 (Suppl. 9), ix162 (2006).
Dileo, P. et al. Updated results from a 'treatment-use' trial of sunitinib in advanced gastrointestinal stromal tumor (GIST). Ann. Oncol. 17 (Suppl. 9), ix162 (2006).
Miller, K. D. et al. Safety and efficacy of sunitinib malate (SU11248) as second-line therapy in metastatic breast cancer (MBC) patients: preliminary results from a Phase II study. Eur. J. Cancer Suppl. 3, 113–114 (2005).
Kulke, M. et al. Results of a Phase II study with sunitinib malate (SU11248) in patients (pts) with advanced neuroendocrine tumours (NETS). Eur. J. Cancer Suppl. 3,204 (2005).
Socinski, M. A. et al. Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): preliminary results of a multicenter Phase II trial. J. Clin. Oncol. 24 (Suppl. 18),7001 (2006).
Socinski, M. A. et al. Efficacy and safety of sunitinib in a multicenter Phase II trial of previously treated, advanced non-small cell lung cancer (NSCLC). Ann. Oncol. 17 (Suppl. 9), ix218 (2006).
Faivre, S. et al. Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC). J. Clin. Oncol. 25 (Suppl. 18), 3546 (2007).
Blay, J-Y . et al. Clinical benefit of continuous daily dosing of sunitinib in patients (pts) with advanced gastrointestinal stromal tumor (GIST). Ann. Oncol. 17 (Suppl. 9), ix163 (2006).
Escudier, B. et al. Continuous daily administration of sunitinib malate (SU11248) – a Phase II study in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (mRCC). Ann. Oncol. 17 (Suppl. 9), ix144 (2006).
Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).
Debiec-Rychter, M. et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on Phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur. J. Cancer. 40, 689–695 (2004).
Morimoto, A. M. et al. Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor. Oncogene 23, 1618–1626 (2004).
Jubb, A. M, Oates, A. J., Holden, S. & Koeppen, H. Predicting benefits from anti-angiogenic agents in malignancy. Nature Rev. Cancer 6, 626–635 (2006). A comprehensive review summarizing the recent findings on potential biological and radiological end points that may be considered to predict benefit from anti-angiogenic therapy.
DePrimo, S. et al. The multitargeted kinase inhibitor sunitinib malate (SU11248): soluble protein biomarkers of pharmacodynamic activity in patients with metastatic renal cell cancer. Eur. J. Cancer. Suppl. 3,420 (2005).
Bello, C. et al. Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3. J. Clin. Oncol. 24 (Suppl. 18), 4045 (2006).
DePrimo, S. E. et al. Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulating plasma levels of VEGF, soluble VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer. J. Clin. Oncol. 24 (Suppl. 18), 578 (2006).
Norden-Zfoni, A. et al. Circulating endothelial cells and monocytes as markers of sunitinib malate (SU11248) activity in patients with imatinib mesylate-resistant GIST. Eur. J. Cancer Suppl. 3, 423 (2005).
Van den Abbeele, A. D. et al. FDG-PET imaging demonstrates kinase target inhibition by sunitinib malate (SU11248) in GIST patients resistant to or intolerant of imatinib mesylate. Eur. J. Cancer Suppl. 3, 202–203 (2005).
Davis D. W. et al. Receptor tyrosine kinase activity and apoptosis in gastrointestinal stromal tumors: a pharmacodynamic analysis of response to sunitinib malate (SU11248) therapy. Eur. J. Cancer Suppl. 3, 203 (2005).
Bukowski R. M. et al. Final results of the randomized Phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis. J. Clin. Oncol. 25 (Suppl. 18),5023 (2007).
Abou-alfa J. K. et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol, 24, 4293–4300 (2006).
Casanovas, O., Hickling, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF-signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005). An important contribution on how tumours may escape from VEGF/VEGFR inhibition, and the potential implication of FGF/FGFR.
Huang, J. et al. Vascular remodeling tumors that recur during chronic suppression of angiogenesis. Mol. Cancer Res. 2, 36–42 (2004). An interesting paper investigating the role of PDGFR in animal models exposed to VEGF/VEGFR inhibition.
Ronnen, E. A. et al. A Phase I study of sunitinib malate (SU11248) in combination with gefitinib in patients with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 24,4537 (2006).
Verhoef, C., de Wilt, J. H. W. & Verheul, H. M. W. Angiogenesis inhibitors: perspectives for medical, surgical and radiation oncology. Curr. Pharm. Des. 12, 2623–2630 (2006).
Raut, C. P. et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J. Clin. Oncol. 24, 2325–2331 (2006).
Acknowledgements
The authors would like to thank E. Eaton for medical writing assistance in the preparation of this manuscript.
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S.F., G.M. and E.R. are all consultants for Pfizer. W.S. was a former employee of Pfizer.
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Supplementary information S1 (table)
Summary of adverse events in the Phase III placebo-controlled GIST study (4/2 schedule of treatment administration). (PDF 168 kb)
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Glossary
- Angiogenesis
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The formation of new blood vessels from pre-existing ones. Also termed neovascularization.
- Receptor tyrosine kinases
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A family of transmembrane receptors that are physiologically activated by the extracellular binding of growth factor(s), and which initiate intracellular signalling.
- Imatinib
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(Gleevec; Novartis). An inhibitor of BCR–ABL, stem-cell factor receptor (KIT) and platelet-derived growth factor receptor (PDGFR). Approved for Philadelphia-chromosome-positive chronic myeloid leukaemia and KIT-positive unresectable/metastatic gastrointestinal stromal tumour (GIST).
- Erlotinib
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(Tarceva; Genentech/OSI Pharmaceuticals). An inhibitor of epidermal growth factor receptor (EGFR). Approved for second-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC).
- Gefitinib
-
(Iressa; AstraZeneca). An inhibitor of EGFR. Approved as monotherapy for continued treatment of locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.
- Sorafenib
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(Nexavar; Bayer/Onyx). An inhibitor of vascular endothelial growth factor receptor (VEGFR2 and VEGFR3), PDGFRβ, KIT, fms-like tyrosine kinase 3 (FLT3), RAF1 and BRAF kinases. Approved for advanced renal cell carcinoma (RCC).
- Sunitinib
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(Sutent; Pfizer). An inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, KIT, FLT3, RET and colony-stimulating factor receptor 1 (CSF1R). Approved for advanced RCC and imatinib-refractory GIST.
- Pericytes
-
Cells related to vascular smooth muscle that are adjacent to and surround the endothelium, share a common basement membrane with the endothelium and have gap-junction connections with the endothelial cells.
- Tumour-associated macrophages
-
Monocytes are continually recruited into tumours and differentiate into tumour-associated macrophages. These accumulate in hypoxic areas and can upregulate transcription factors, which in turn activate various mitogenic, pro-invasive, pro-angiogenic and pro-metastatic genes.
- Oncogene
-
A mutated and/or overexpressed version of a normal gene that in a dominant manner can release the cell from the normal restraints of growth and thus, alone or together with other changes, convert a cell into a tumour cell.
- Hypoxia-inducible transcription factor 1
-
(HIF1). A heterodimeric transcription factor that has a key role in the response to hypoxic stress. It is composed of HIFα and HIFβ subunits (HIFα has at least three isoforms: HIFα, HIFα and HIFα).
- von Hippel–Lindau
-
(VHL). A tumour suppressor gene that is an important regulator of HIF. In renal cell carcinoma, defective function of VHL ablates proteolytic regulation of HIFα and HIFα, leading to constitutive activation of hypoxia pathways.
- Endothelial progenitor cells
-
Undifferentiated cells in the adult bone marrow that can travel through the blood to sites of ongoing angiogenesis, and differentiate into mature endothelial cells.
- Vasculogenesis
-
The formation of new blood vessels within previously avascular tissue.
- Cytogenetic abnormalities
-
Abnormalities in chromosomal DNA (karyotype).
- Lymphangiogenesis
-
Lymphatic vascular structures organized to collect extravased fluids, macromolecules and leukocytes at regional lymph nodes.
- Hypoxia-induced necrosis
-
The accidental death of cells and living tissue due to oxygen depletion.
- 4/2 schedule
-
A four weeks on treatment, two weeks off treatment cycle.
- Objective response rate
-
(ORR). The proportion of patients with complete or partial responses. Clinical response (complete response, partial response, stable disease and progressive disease) was assessed according to response evaluation criteria in solid tumours (RECIST).
- Hand–foot syndrome
-
Characterized by tingling and/or numbness, swelling and redness of the palms and soles. In severe cases, the skin may peel, develop ulcerations or blisters and cause severe pain. Also known as palmar–plantar erythrodysesthesia.
- Grade
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The severity of adverse events is categorized according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2.0 and Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (grade 1 is the least severe and 4 is the most severe).
- RECIST criteria
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Response evaluation criteria in solid tumours (RECIST) are used to evaluate the antitumour activity of novel anticancer agents in clinical trials. Evaluation of the tumour is made according to the longer diameters of target lesions.
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Faivre, S., Demetri, G., Sargent, W. et al. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6, 734–745 (2007). https://doi.org/10.1038/nrd2380
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DOI: https://doi.org/10.1038/nrd2380
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