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Introduction
Renal cell carcinoma (RCC) is the most lethal of the urological cancers and accounts for about 3% of all malignancies in adults, with about 300, 000 new cases per year and about 120, 000 deaths per year worldwide [1-3]. As it is most common in older men, active and passive cigarette smoking, obesity and hypertension are known risk factors although most patients do not have an identifiable risk factor; and the pathogenic mechanisms underlying the established risk factors remain unclear [1, 2]. Nonetheless, about 2–3% of RCC are associated with familial and several autosomal dominant syndromes, most notably von Hippel-Lindau (VHL) syndrome [4] and hereditary papillary renal carcinoma (HPRC) [3, 5, 6]. While Patients with RCC can present with local or systemic symptoms, many cases are symptomless until the stage is advanced, including flank pain, blood in the urine, or a lump in the abdomen [1, 2]. Pathologically, RCC comprises a heterogeneous group of cancers with diverse genetic and molecular alterations, each derived from the various parts of the nephron and possessing distinct genetic characteristics, histological features, and clinical phenotypes [1, 2, 6, 7]. Clear cell renal cell carcinoma accounts for about 70-80% of all RCC while papillary RCC represents about 10-15% of renal cancer [1, 2]. Other rare subtypes include papillary adenoma, multilocular cystic clear-cell carcinoma, hybrid oncocytic chromophobe tumor, carcinoma of the collecting ducts of Bellini, renal medullary carcinoma, carcinoma associated with neuroblastoma, and mucinous tubular and spindle-cell carcinoma [1-3]. Although RCC can be sporadic or hereditary, and VHL mutations only occur in a small fraction of RCC, a majority is driven by dysfunction of the von Hippel-Lindau (VHL) gene function, which leads to aberrant activation of the hypoxic response and neoangiogenesis [2, 3, 7].
While nephrectomy remains an importafnt intervention for localized RCC, systemic therapy is the mainstay of treatment for the patients with relapsed and/or metastatic RCC [1, 8, 9]. Despite recent advances in diagnostic imaging, surgical therapy and basic molecular understanding, many patients still experience metastatic disease, and their response rates to conventional therapies rarely exceed 25%, yet associated with serious adverse effects [1, 8, 10]. For the past decade, the therapeutic landscape of RCC has significantly expanded, mostly driven by targeting the dysregulated metabolic pathways involved in oxygen...