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Pazopanib: An Overview of its Development as a Therapy for Patients with Metastatic Renal Cell Carcinoma

Ronald M Bukowski, MD1,2

Angiogenesis is a valid therapeutic target in renal cell carcinoma (RCC), particularly in relation to the vascular endothelial growth factor (VEGF) signaling axis. Clear-cell carcinoma of the kidney is now recognized as a malignancy that is sensitive to inhibitors of the VEGF pathway. Several genetic and molecular factors may be responsible for this, including loss of heterozygosity and mutation of the von Hippel–Lindau (VHL) gene allele (>80%) in sporadic tumors [1]. The normal function of the VHL protein is to form an intracellular protein complex to polyubiquinate hypoxia-inducible factor-α (HIF-α) and then promote its destruction in the proteasome [2]. When VHL protein is non-functional or absent, this nuclear transcription factor accumulates and binds with HIF-β to form a complex responsible for the induction of a variety of genes, including VEGF and platelet-derived growth factor (PDGF). The observation of overproduction of growth factors such as VEGF and PDGF and overexpression of their receptors (VEGFR and PDGFR) in RCC led to development of a new treatment paradigm for metastatic disease. Tyrosine kinase inhibitors (TKIs), such as pazopanib, that interfere with VEGFR and PDGFR phosphorylation have been shown to inhibit the growth and spread of RCC in both preclinical and clinical studies [3–5]. A Phase II clinical trial of pazopanib demonstrated promising activity accompanied by a favorable toxicity profile in treatment-naïve or cytokine/bevacizumab-pretreated RCC patients [4]. A subsequent, placebo-controlled, Phase III trial in untreated or cytokine-treated patients with advanced RCC demonstrated a significant improvement in progression-free survival (PFS) with pazopanib [5]. The purpose of this report is to review the studies of pazopanib published to date, with a particular focus on its potential use in advanced RCC patients and its future development for the treatment of this neoplasm.

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