© 2008 THE AUTHORS JOURNAL COMPILATION © 2 0 0 8 B J U I N T E R N A T I O N A L | 1 0 1 , 1 3 3 9 – 1 3 4 2 | doi:10.1111/j.1464-410X.2008.07506.x 1339 2008 The AUTHORS Mini Review SUNITINIB THERAPY IN RCC O’BRIEN ET AL. Sunitinib therapy in renal cell carcinoma Matthew F. O’Brien, Paul Russo and Robert J. Motzer* Urology Service, Department of Surgery, and *Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Accepted for publication 29 November 2007 mutation of the VHL gene on chromosome 3 [10]. In addition, nearly 90% of sporadic clear cell RCC had similar functional loss. The cloning of this tumour-suppressor gene and the identification of its role in growth factor- associated angiogenesis has provided an insight into the biology of RCC [11]. The VHL gene normally regulates the degradation of hypoxia inducible-factor- α (HIF- α ). When the VHL gene function is absent HIF- α accumulates, resulting in unregulated expression of hypoxia-inducible gene products such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) [12]. These growth factors are secreted and bind to their specific tyrosine kinase (TK) receptors, resulting in cell proliferation, migration and survival. This promotes tumour angiogenesis in an effort to reverse the apparent hypoxia and facilitates tumour growth. Therefore, inhibition of these angiogenic signalling pathways was proposed as a promising clinical therapeutic option and prompted clinical studies with novel targeted agents [11,12]. Many therapies have been designed and tested based on inhibition of VEGF, including recombinant human monoclonal antibody against VEGF (bevacizumab) and VEGF TK receptor (-R) inhibitors (sorafenib, sunitinib and pazopanib). In this review we concentrate on one such VEGF-R and PDGF-R inhibitor, sunitinib. BACKGROUND TO SUNITINIB Sunitinib (SU11248; Sutent Pfizer, Inc. La Jolla, CA, USA) is an orally available, highly potent selective inhibitor of certain TKs including VEGF-R types 1–3 and PDGF-R types α and β [13]. These receptors have pivotal roles in the pathogenesis of many tumours, including RCC. Pre-clinical studies evaluated the effect of sunitinib in biochemical and cellular assays and models. In vitro assays showed inhibition of VEGF-induced proliferation of endothelial cells and PDGF-induced proliferation of mouse fibroblasts cells [13]. Rodent xenograft models involving the oral administration of sunitinib showed in vivo dose-dependent antitumour effects. Growth was inhibited in implanted solid tumours. Furthermore, large established tumours were eradicated in a carcinogen-induced tumour model and in an experimental disease dissemination model that mimics clinical metastatic disease [13]. These studies resulted in several phase I studies to investigate the safety and dosage of sunitinib for phase II therapeutic trials. EARLY DOSE-FINDING STUDIES Phase I studies in patients with advanced solid tumours, imatinib-refractory gastrointestinal tumours and advanced leukaemia established the dosing regimens for sunitinib [14]. These studies showed partial responses in patients with advanced RCC. Dosages ranged were 50–150 mg/day orally in ‘4-weeks on/2-weeks off’ regimen. Therapeutic plasma concentrations were achieved with doses of ≥ 50 mg/day and accumulation of both the drug and its active metabolite on continuous daily-dosing KEYWORDS clear cell carcinoma, platelet-derived growth factor inhibitor, progression-free survival, RCC, sunitinib, vascular endothelial growth factor inhibitor INTRODUCTION RCC is the most common cancer of the kidney and accounts for almost 7000 new cases of cancer and more than 3600 deaths annually in the UK, and > 51 000 cases and 12 900 deaths in the USA [1,2]. Up to a third of patients who are diagnosed with RCC present with metastatic disease, and ≈ 40% of those who have attempted curative therapy for localized disease develop recurrence [3,4]. Until recently, the treatment options for patients with metastatic disease were limited to immunotherapy regimens based on interleukin-2 or interferon- α , as RCC is highly resistant to chemotherapy. However, response rates with such cytokine therapy are low (10–15%), with a median survival of 13 months at best [5–8]. There had been no effective treatment for patients whose disease progressed after initial cytokine-based therapy. The response rates were < 5% with second-line regimens [9]. There are several distinct histological subtypes of RCC, but > 80% are classified as clear cell carcinoma [3]. The high frequency of clear cell RCC in Von Hippel-Lindau (VHL) syndrome led to cytogenetic studies that identified the early loss of function or