The development of targeted therapy for renal cell carcinoma

Over 85% of kidney and renal pelvis cancers are renal cell carcinomas (RCC); a disease with multiple subtypes including clear cell, papillary, chromophobe and oncocytomic. The variable nature of RCC makes one blanket treatment impossible, and therefore targeted therapies may be more effective at enhancing survival. A recent review from Randall et al., (2014) summarises the current knowledge on RCC genetic aberrations and their effects, as well as discussing current and future treatment options.

The majority (>80%) of sporadic RCC cases are clear cell RCC (ccRCC), often with increased risk of metastatic spread, associated with mutations in the VHL, PBRM, SETD2 and BAP1 genes although mutations in over 30 other genes have also been found including TP53, PTEN and occasionally FLCN. The loss of VHL leads to a reduction in HIF repression and subsequent changes in transcription, including overexpression of VEGF, PDGF-β, TGF-α and erythropoietin, results in vascularised tumour growth. Disruption in HIF signalling and changes in cellular metabolism have also been identified as a result of FLCN loss (Preston et al., 2011).

Currently the molecular drivers of papillary RCC (10-15% of cases), chromophobe RCC (5%) and renal oncocytomas (3-5%) are less well understood. These subtypes generally have a better prognosis as they are slower growing, chromophobe RCCs in particular.

Cases of inherited RCC are seen in BHD patients although the histology of these RCC tumours is highly variable, and dissimilar to sporadic RCC. ccRCC is seen in comparatively fewer cases (~9%), and in addition hybrids of clear cell/papillary and clear cell/chromophobe RCCs have been reported. Such tumours of a clear cell nature have been shown to metastasise in BHD patients and often result in increased mortality. The majority of BHD-RCC tumours however are slow growing chromophobe RCCs (34%) or have a hybrid chromophobe/oncocytoma histology (50%), and can be surgically managed. It is also not uncommon for tumours of several different subtypes can be found within the same kidney (Hudon et al., 2010, Kuroda et al., 2014).

Increasing understanding of the molecular pathways perturbed in RCCs can enhance the use of targeted therapies. The majority of ccRCC cases are currently treated with VEGF-inhibitors such as the tyrosine kinase inhibitor sunitinib. However in cases where there is an additional disruption to the PI3K-AKT-mTOR signalling pathways there has been some success using mTOR inhibitors such as everolimus (Hudes et al., 2007).

Future development of effective RCC treatments would be improved with patient selection based on molecular analysis of the tumours. Previous trials have shown marked differences in survival between unselected cohorts and subsets of patients with the same germline mutations (Chouieri et al., 2013). Even with well-established drugs it has been shown that the likelihood of a response can be predicted based on molecular expression patterns (Dornbusch et al., 2013). Beuselinck et al., 2015 recently reported that multi-omic analysis of ccRCC tumours could be used to predict response to sunitinib, with significant variation in progression-free survival and overall survival between subgroups.

BHD-RCC tumours are morphologically similar to sporadic chromophobe RCCs and renal oncocytomas and both types show an increase in expression of mitochondrial and oxidative phosphorylation associated genes (Klomp et al., 2010,). In BHD this is associated with an increase in PGC1α-activation (discussed in an alternative context in last week’s blog) and aberrant activation of the mTOR pathway. As a result rapamycin can be used to treat local recurrence and metastases in BHD patients (Kuroda et al., 2014). Further information on the molecular pathogenesis in both sporadic and inherited RCCs will make it possible to develop more targeted treatments in the future.

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