Rationale for targeted therapies and potential role of pazopanib in advanced renal cell carcinoma

Abstract

Advanced renal cell carcinoma (RCC) remains a challenging, major health problem. Recent advances in understanding the fundamental biology underlying one form of RCC, ie, clear cell (or conventional) RCC, have opened the door to a series of targeted agents, such as the tyrosine kinase inhibitors (TKIs), which have become the standard of care in managing advanced clear cell RCC. Among the newest of these agents to receive Food and Drug Administration approval in this disease is pazopanib. This review will summarize what is known about the fundamental biology that underlies clear cell RCC, the data surrounding the previously approved targeted agents for this disease, including not only the TKIs but also the mTOR inhibitors and the vascular endothelial growth factor-specific agent, bevacizumab, and the newest TKI, pazopanib. It will also explore the potential role for pazopanib relative to the other available agents and where it may fit into the armamentarium for treatment of advanced/metastatic RCC.

Keywords: clear cell renal cell carcinoma; pazopanib; targeted therapy; tyrosine kinase inhibitor.

Figure 1

Biology of the von Hippel-Lindau/hypoxia-inducible factor (VHL-HIF) axis in the setting of hypoxia or a mutation or aberration of the VHL gene product. In normoxic conditions, HIFα is hydroxylated on specific proline residues by prolyl-hydroxylases. VHL acts as the sensor for these hydroxylated proline residues as part of the VHL-E3 ubiquitin ligase. This polyubiquitinates HIFα and marks it for degradation by the proteasome. In hypoxic conditions (or in the presence of aberrant VHL), HIFα is allowed to accumulate in the cell. It associates with HIFβ and this complex translocates to the nucleus and acts as a transcription factor binding to hypoxia response elements and upregulating oxygen-sensitive genes. These HIF-responsive genes include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGFα), glucose transporter-1 (GLUT1), carbonic anhydrase IX (CA-IX), erythropoietin (EPO), and others. Examples of selected receptors are given, including VEGF receptor (VEGFR), PDGF receptor (PDGFR), and the receptor for TNFα and epidermal growth factor receptor (EGFR). Shown is the downstream signaling for one of these receptors, VEGFR, including through the PI3 kinase (PI3K)/AKT/mTOR, p38 MAP kinase (p38MAPK), and RAS/RAF/MEK/ERK pathways. Examples of agents (including pazopanib) that impact on this cascade are given, and where they act on the pathway is shown.