Current Perspectives in Metastatic Renal Cell Carcinoma Treatment: The Role of Mammalian Target of Rapamycin (mTOR) Inhibition

Abstract

Renal cell carcinoma (RCC) is the most frequently occurringrenalmalignancy,anditsincidenceisincreasingbothintheUnited States and in parts of Europe [1–3]. Approximately25% of patients present with metastatic RCC (mRCC) atdiagnosis [4], while 20–30% of patients with localizedtumours at the time of nephrectomy relapse after surgeryand develop metastasis [5]. Furthermore, mRCC has a poorprognosis and is notoriously resistant to treatment withchemotherapy [2].Research into the underlying biology and genetics ofRCC has led to the identification of two main signallingcascadesthathave apivotalrole in the developmentofthedisease: the von Hippel-Lindau/hypoxia-inducible factorpathway and the mammalian target of rapamycin (mTOR)pathway [6,7]. Subsequently, novel therapies have beendeveloped to specifically target key components of thesesignalling pathways involved in tumour growth andangiogenesis[7]. Targeted drugs are becoming the recom-mended first- and second-line treatment options forpatientswithmRCC,replacingstandardcytokinetherapiesthat have been major constituents in the management ofmRCC since the 1990s [7]. Because of their selectivity,targeted agents are generally better tolerated thanstandard cytotoxic treatments [8]. Results from clinicalstudies have shown positive efficacy in mRCC followingtreatment with targeted therapy such as sunitinib [9],sorafenib [10], temsirolimus [11], and the combination ofbevacizumab with interferona [12,13];alloftheseagentshavebeenapprovedforuseinmRCC.Everolimus(RAD001),an oral mTOR inhibitor, has also shown activity in thetreatment of mRCC, especially in patients who progressedon previous treatment with vascular endothelial growthfactor (VEGF)–targeted therapy [14].Everolimuswasapproved in March 2009 by the US Food and DrugAdministration for treatment of patients with advancedRCC after failure of treatment with sunitinib or sorafenib.European Union approval for use of everolimus in patientswith advanced RCC whose disease progressed on or aftertreatment with VEGF-targeted therapy was granted inAugust 2009.Novel therapies have the potential to help reduce theclinical burden of mRCC [2], and continued development ofdrugs targeting different molecules and pathways involvedinthepathologyofmRCChavethepotentialtoprovideevenmore effective treatment options for clinicians and anincreased benefit for patients. Prognostic and risk factorsaffect clinical outcomes and facilitate the selection of thosepatients most likely to respond to treatment with targetedtherapies [15,16]. Therefore, treatment algorithms arehelpful for determining which patients should receive aparticular therapy regimen at a given time point, accordingto individual patient profiles.This supplement discusses the current medical land-scape for mRCC with particular emphasis on epidemiology,molecular tumourigenic pathways, and current and futuretreatment options. Recent updates to treatment algorithms(including encouraging data from trials involving ever-olimus)thathelpoptimize futureclinicaloutcomesare also