**1. Introduction**

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and close to 90% of all renal neoplasms. Renal cell carcinomas, by definition, are tumors that originate in the renal cortex. These tumors are often asymptomatic, have diverse clinical manifestations, and can be associated with hereditary syndromes. Surgery is the treatment of choice for localized RCC. In localized RCC, partial nephrectomy for small tumors and radical nephrec‐ tomy for larger tumors continue to be the gold standard. Surgical practice has reduced morbidity and has advanced toward more limited and less invasive resection approaches. In addition, cytoreductive nephrectomy is often indicated before embarking on systemic treatment in patients with metastatic disease.

In recent years, there has been a shift from radical nephrectomy toward more nephron-sparing approaches. RCC still remains a predominantly surgical disease because RCCs are frequently characterized as tumors that are resistant to chemotherapy and radiation. However, advances in the treatment of metastatic RCC have evolved, primarily with biologic response modifiers.

The management of RCC has undergone the most significant transformation. Scientific understanding of the molecular basis of cancer and the role of growth factors have resulted in the identification of signaling pathways relevant in the pathogenesis of renal cell carcinoma. This knowledge provided the impetus for developing new drugs that target and inhibit these diff e rent pathways. Previously, systemic therapy for renal cancer has been limited to the use of interleukin-2 and the off-label use of interferon. These drugs formulated an immunothera‐ peutic approach to the treatment of advanced renal cancer. Translational research and participation of patients with advanced renal cell carcinoma in clinical trials have resulted in

© 2013 Michalaki et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Michalaki et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the approval of six systemic targeted therapies. These include sorafenib tosylate, sunitinib malate, temsirolimus, everolimus, bevacizumab in combination with interferon, and most recently, pazopanib. Each of these drugs has increased therapeutic options and appears to prolong survival for patients with advanced renal cancer.

eukaryotic translation initiation factor 4E binding protein-1 (eIF-4BP1) and ribosomal S6 kinase (p70s6k). This leads to the synthesis of cellular proliferation proteins such as cyclin D1, angiogenesis mediators such as VEGF, and hypoxia response regulators such as HIF1alpha [5].

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

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Systematic studies of cell lines in which pVHL or HIF status has been manipulated suggest that as many as 100 HIF-responsive genes might be dysregulated when pVHL is crippled [6]. A number of these genes encode proteins that are implicated in tumorigenesis. This makes them amenable to pharmacologic attack. Evidence now indicates that targeting these HIF-

Fortunately, a number of drugs have been identified that indirectly downregulate HIF protein levels. One such drug, rapamycin, inhibits mTOR, which plays a critical role in the regulation of protein translation. This in turn affects HIFα, which is very sensitive to changes in protein translation due in part to its high metabolic turnover rate. Inhibitors of mammalian target of

Clear cell renal carcinomas are notoriously angiogenic. Indeed, prior to the availability of computed tomography, renal angiograms were often used to diagnose these tumors. Renal carcinomas overproduce a variety of angiogenic moieties including vascular endothelial growth factor (VEGF), the product of a HIF-responsive gene. In addition to promoting angiogenesis, VEGF might suppress antitumor immune responses as well. It has also been suggested that VEGF has direct stimulatory effects on renal carcinoma cells, although these

Several drugs that inhibit VEGF, or its kinase insert domain-containing receptor (KDR), have activity against clear cell renal carcinomas. In a randomized phase II study, patients with metastatic renal carcinoma who were treated with 10 mg/kg (but not 3 mg/kg) bevacizumab, a neutralizing antibody against VEGF, exhibited a significant delay in time-to-disease pro‐ gression, [10]. Other unrelated KDR inhibitors such as SU11248 (sunitinib maleate), BAY43-9006 (sorafenib), and AG-013736 also appear to have significant activity against this

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

responsive genes can alter the natural history of human renal carcinoma.

rapamycin (mTOR) like rapamycin, downregulate HIF, [7].

**4. Targeting HIF-responsive growth factors**

**4.1. Vascular endothelial growth factor**

findings await further corroboration, [8, 9].

**5. VEGFR tyrosine kinase inhibitors**

tumor subtype, [11, 12].

**3. Targeted therapies**
