**5. VEGFR tyrosine kinase inhibitors**

VEGF stimulates endothelial cell proliferation and survival. Immature blood vessels appear to be exquisitely sensitive to VEGF withdrawal. In contrast, mature blood vessels are less sensitive to VEGF withdrawal because their endothelial cells are responsive to additional survival factors such as platelet-derived growth factor (PDGF) released from surrounding pericytes. Ongoing efforts to improve our understanding of the basic biology of RCC have identified several potential targets for therapeutic modulation. One particularly promising area of investigation is the role of VEGF in the pathogenesis of renal cell carcinoma. VEGF is a tumor-secreted cytokine that plays an important role in both normal and tumor-associated angiogenesis. VEGF exerts its biologic effect by binding to cell surface VEGF receptors, thereby inducing dimerization and autophosphorylation of intracellular receptor tyrosine kinases, leading to activation of downstream signal transduction elements. There are several forms of VEGF receptors (VEGFR), but VEGFR-2 appears to be the main receptor responsible for the proangiogenic effects of VEGF. The relevance of VEGF to tumor biology is supported by the high incidence of von Hippel-Lindau tumor suppressor gene mutations in patients with RCC, which subsequently leads to increases in VEGF expression. Receptor tyrosine kinases (RTKs) play an integral role in the signaling cascade of VEGF and PDGF [12].

prognostic criteria, the HR of death for sunitinib versus IFN was 0.049 (p=0.001). Even those patients classified as having a poor prognosis by MSKCC criteria had a survival advantage. Current treatment algorithm for patients with met (10.7 versus 4.1 months, p=0.0329), sug‐

Current Perspectives in Metastatic Renal Cell Carcinoma Treatment: The Role of Targeted Therapies

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Sorafenib is an oral multikinase inhibitor that inhibits vascular endothelial growth factor (VEGF) receptors 1-3, platelet-derived growth factor receptor (PDGFR)–ß, and the serine threonine kinase Raf-1 [18]. A phase III trial of sorafenib randomized 905 treatment-refractory metastatic RCC patients to sorafenib 400 mg orally twice daily or placebo [19]. In the sorafenib arm, a progression-free survival (PFS) advantage of 5.5 months vs 2.8 months was observed (hazard ratio for disease progression: 0.44; 95% confidence interval: 0.35-0.55; P <.01). The median overall survival was also increased for patients in the sorafenib group (19.3 vs 15.9 months) but did not reach prespecified statistical boundaries for significance. The common toxicities experienced with sorafenib are similar to sunitinib except that the hand-foot syn‐ drome may be more pronounced and cardiotoxicity and fatigue appears to occur less fre‐ quently. Based on these data, sorafenib has been FDA approved and become a standard of care for second-line treatment of mRCC after immunotherapy failure. However, a smaller, random‐ ized phase II of sorafenib vs interferon alfa-2b in 189 previously untreated metastatic RCC patients failed to demonstrate a PFS advantage over IFN. Compared with interferon alfa-2b, sorafenib did not significantly improve the median PFS (5.6 vs 5.7 months, respectively), [20]. Although the reason for the lack of significant effect when compared with interferon alfa-2b in the frontline setting remains unclear, one possibility is that it is because of a weaker inhibition of VEGF receptor compared with sunitinib. Although there may be patients in whom sorafenib is a preferred initial agent because of the toxicity profile or other considerations, sorafenib has largely been relegated to second-line and later therapy. The identification of those patients for whom sorafenib would be the preferred frontline treatment is needed.

gesting that use of sunitinib is beneficial in this population as well.

**8. Mammalian Target of Rapamycin (mTOR) inhibitors**

cated in multiple tumor-promoting intracellular signaling pathways.

Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR), a molecule impli‐

Activation of the mTOR protein, through cellular stimuli-triggered activation of the PI3K/Akt pathway, can also result in HIF accumulation. mTOR phosphorylates and activates p70S6K, which results in enhanced translation of certain proteins, including HIF. Activated HIF translocates into the nucleus, where it triggers the transcription of a large number of hypoxiainducible genes; among these are the growth factors vascular endothelial growth factor (VEGF) and PDGF. These growth factors interact with their respective cell-surface receptors, leading to cell migration, proliferation, and permeability. Temsirolimus and everolimus bind to the

**7. Sorafenib**

RTKs have an extracellular domain that binds to their respective ligand and an intracellular domain that holds the tyrosine kinase responsible for downstream signaling. Upon ligand binding, the RTKs dimerize or multimerize to induce a conformational change that allows ATP binding resulting in autophosphorylation and transphosphorylation. These tyrosine domains are then able to phosphorylate and activate various proteins in the downstream signal transduction cascade.
