**2. Biologic basis of targeted therapy**

Recent advancements in the understanding of the genetics of RCC have led to a new patho‐ logical classification of five different subtypes of RCCs: clear cell, papillary, chromophobe, collecting duct carcinoma (Bellini Duct tumor), and renal carcinoma unclassified (renal medullary carcinoma). This classification is primarily based on cytologic appearance and the cell origin in combination with growth pattern and genetic alterations [1].

The grading of RCC is based on the morphology of a neoplasm with hematoxylin and eosin (H&E) staining on microscopy. The most popular and widely used system for grading RCC is a nuclear grading system described by Fuhrman, Lasky, and Limas in 1982. This system categorizes RCC into one of four grades based on nuclear characteristics and has been shown to correlate with prognosis.

Adenocarcinomas represent the great majority (85%) of renal cell cancers. Adenocarcinomas may be subdivided into clear cell renal carcinomas, the most common form of kidney cancer; Many cases of clear cell carcinoma are linked to inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), [2]. VHL is a 213 amino acid protein that polyubiquinates hypoxiainducible factor 1 alpha (HIF1alpha) which marks it for destruction by the cellular proteosome. Normally, low oxygen conditions allow HIF1alpha to accumulate and bind to HIF1beta thereby creating a complex that transcriptionally activates genes. In patients with aberrant VHL, HIF1alpha is left to accumulate freely without degradation even under normal oxygen conditions and thus the transcription of genes related to glucose metabolism, apoptosis, angiogenesis and endothelial stabilization are abnormally promoted. This disordered response to hypoxia activates over 100 HIF-responsive genes which include growth factors and their receptors such as VEGF, platelet-derived growth factor (PDGF), and transforming growth factor alpha/beta (TGF), [3].

1nactivation of the VHL gene is an early step in clear cell renal carcinogenesis, at least for those tumors associated with VHL disease. Subsequent studies have shown that VHL inactivation is also common in non-hereditary clear cell renal carcinoma. Approximately 50% of sporadic clear cell renal carcinomas harbor somatic mutations affecting the maternal and paternal VHL locus.

Another downstream effect of the VEGF receptor (VEGFR) pathway is the activation of PI3 kinase and Akt which in turn promote mTOR kinase [4]. mTOR is a central component of intracellular pathways that promote tumor growth and proliferation, cellular metabolism and is a mediator of the hypoxic response as an upstream activator of HIF1alpha. When mTOR and raptor combine to form an activated complex, they phosphorylate and thus activate the 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].
