**2. Molecular pathogenesis**

### **2.1. Clear- cell variants renal cell carcinoma**

The discovery of von Hippel–Lindau (VHL) / hypoxia-inducible factor (HIF) oxygen-sensing pathway and its role in the pathogenesis of RCC (clear-cell as well as some of the non-clearcell variant), has led to a new approach in the systemic therapy for RCC. [1, 3] Tumour suppressor gene VHL encodes the VHL protein (pVHL), which interacts with hypoxiainducible factor (HIF) to regulate cellular response to oxygen deprivation. HIF is a gene

transcription factor and consists of two subunits: HIF α-subunit and the HIF β-subunit (also known as aryl hydrocarbon receptor nuclear translocator (ARNT) protein). In the presence of normal oxygen tension (or normoxic state), HIF-α is hydroxylated. pVHL-E3 ubiquitin ligase complex targets the hydroxylated HIF-α for proteosomal degradation. [4] VHL protein functions as the substrate-recognition subunit of this complex. [5, 6]

The traditional teaching is that cytoreductive nephrectomy lead to improved outcome from systemic therapy. This is based on phase III data that showed an improvement in response to IFN-α following nephrectomy in the metastatic setting. In the era of targeted therapy / anti-VEGF therapies, the validity of this practice has been called into question. [20] Clinical trials

New Systemic Treatment Approaches for Metastatic Renal Cell Carcinoma

http://dx.doi.org/10.5772/55280

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Beyond surgery, the only systemic options available prior to the era of targeted therapy consisted of interleukin-2 (IL-2) and interferon-α (IFN-α). Other treatments that had been

IFN-α classically caused flu-like syndrome, depression and in some cases suicidal ideation and is certainly onerous especially in the patients with poorer performance status. [1, 22] IL-2, the other cytokine has a small long term survival benefit of 4%. This is however at the cost of potentiallylifethreateningtoxicitiessuchashypotension,oliguria,capillaryleaksyndromewith secondary multi-organ failure, somnolence and confusion. [23] Not surprisingly, the underly‐ ing enthusiasm for cytokine agents as frontline therapy in metastatic RCC has been replaced by tyrosine kinase inhibitors / targeted therapy which has a more favourable toxicity profile. [24]

The targeted therapies used in metastatic RCC consist of 1. Anti-VEGFs, which are monoclonal antibodies that bind directly to VEGF and related peptides and therefore removing them from the circulation (bevacizumab) and 2. Small molecule tyrosine kinase inhibitors (SMTKIs) that target the down-stream tyrosine kinase signaling pathways, are involved in promotion of tumour angiogenesis, endothelial growth, proliferation and ultimately tumour survival and metastasis. [25] The SMTKIs that have been approved for use in 2012 include sunitinib,

Sunitinib is a multi-kinase inhibitor targeting numerous VEGF receptors (VEGF-1, 2, 3) and additionaltyrosinekinase receptors (PDGFR, c-Kit,FLT-3,CSF-1R, andRET)[26-29]Earlytrials showed sunitinib to be effective in patients with advanced malignancies including RCC. [30]

A phase II study of sunitinib in patients with cytokine-refractory metastatic RCC assessed the clinical efficacy and safety of sunitinib as second-line therapy. [31] Sixty three patients who previously failed cytokine-based therapy received 50mg of sunitinib for 4 weeks followed by a 2 week scheduled break, in a 6 week cycle. A partial response of 40% (n=25) (PR) and a stable disease response for ≥ 3 months in 27% (n=17) of the patients were reported. The median time

A second but larger phase II trial of 106 patients similarly confirmed promising activities of sunitinib in cytokine refractory, metastatic RCC. An overall objective response of 44% was observed with 1% (n=1) of patients demonstrated a CR and 44% showed PR. [32] A further

to progression and survival were 8.7 months and 16.4 months respectively. [31]

trialed included chemo- and hormonal therapy have all been discouraging. [21]

are underway to address this very question.

sorafenib, pazopanib and axitinib.

*3.1.1.1. Sunitinib intermittent dosing*

*3.1.1. Sunitinib*

**3.1. Small molecular tyrosine kinase inhibitors**

VHL gene mutation or hypermethylation leads to intracellular accumulation of HIF-α subu‐ nits.[7]HIF-αsubunits,aftertranslocationintothenucleus,actinconcertwiththeHIF-βsubunits, andformtranscriptionalfactor complexes thatinduce transcriptionofhypoxia-response genes. [8] The endpoint is an increase in the production of pro-angiogenic factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor alpha and beta (TGF-α and TGF-β). [9] By increasing angiogenesis through VHL-HIF pathway the tumour increases its potential to survive and progress. [10]

### **2.2. Non clear-cell variant**

Papillary carcinomas are commonly bilateral, multifocal and frequently present as small, early stage tumours. [11] They can be further subdivided histologically into papillary types I and II with underlying different genetics and molecular pathways. [12] Type I papillary renal cancers are linked to activating mutations of the methyl-nitroso-nitroguanidine induced (MET) oncogene. [13] The MET oncogene mutations activate the intracellular kinase domains and subsequently trigger the hepatocyte growth / MET pathway. [13] Type II papillary renal cancers on the other hand are associated with mutations of the fumarate hydratase (FH) tumour suppressor gene. [14] Mutational inactivation of the FH tumour suppressor gene leads to a pseudo-hypoxic state and up-regulation of the HIF α-subunits. The accumulation of fumarate is induced by the mutated FH enzyme. That in turn causes inhibition of HIF-prolyl hydroxylase(HPH), an enzymatic regulator of the intracellular HIF-α. Inactivation of the HPH disrupts the hydroxylation of HIF leading to failure of recognition by pVHL and subsequent VHL-dependent proteosomal degradation of HIFs. Accumulation of HIF leads to overexpression of pro-angiogenic factors and tumour proliferation. [15]

Chromophobe renal cell cancers accounts for 4% of all RCCs. [1] The exact pathogenesis is not established. It is thought that the VEGF-angiogenic pathway is implicated based on the elevated levels of VEGF and its receptors in this type of RCC. The KIT oncogene and the folliculin gene linked to the familial form of chromophobe/oncocytic RCC hybrid (Brit-Hogg-Dubé-Syndrome), are extra molecular targets identified in this variant [16, 17] Collecting duct RCC are very rare and the underlying pathogenesis has not been established. [18]
