Renal cancer biomarkers: the promise of personalized care

Abstract

Significant advances in our understanding of the biology of renal cell carcinoma (RCC) have been achieved in recent years. These insights have led to the introduction of novel targeted therapies, revolutionising the management of patients with advanced disease. Nevertheless, there are still no biomarkers in routine clinical use in RCC. Tools used routinely to determine prognosis have not changed over the past decade; classification remains largely morphology based; and patients continue to be exposed to potentially toxic therapy with no indication of the likelihood of response. Thus the need for biomarkers in RCC is urgent. Here, we focus on recent advances in our understanding of the genetics and epigenetics of RCC, and the potential for such knowledge to provide novel markers and therapeutic targets. We highlight on-going research that is likely to deliver further candidate markers as well as generating large, well-annotated sample banks that will facilitate future studies. It is imperative that promising candidates are validated using these resources, and in subsequent prospective clinical trials, so that future biomarkers may be used in the clinic to personalize patient care.

Figure 1

Biological pathways targeted for therapy in renal cell carcinoma based on a knowledge of the underlying genetic changes and downstream biological consequences. Loss of function of the VHL tumour suppressor gene leads to stabilisation of hypoxia-inducible factor alpha (HIFα). Activated HIF translocates into the nucleus and leads to the transcription of a large number of hypoxia-inducible genes including vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). Mammalian target of rapamycin (mTOR) is a kinase within the PI3K/Akt pathway that can promote cell growth and survival pathways as well as causing accumulation of HIF. Bevacizumab is a monoclonal antibody to VEGF whilst sunitinib, sorafenib, axitinib and pazopanib are VEGF receptor tyrosine kinase inhibitors. These agents are thought to primarily function as antiangiogenic agents, inhibiting ligand binding or downstream receptor signalling of VEGF and PDGF on endothelial cells. Temsirolimus and everolimus inhibit the kinase activity of the mTOR complex 1 (mTORC1). Reproduced with permission from Elsevier©. From [66]. HIF: hypoxia-inducible factor; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; PDGF: platelet derived growth factor; PTEN: phosphatase and tensin homolog; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

Figure 2

Cancer Genomics of the Kidney (CAGEKID) study schema. RCC: renal cell carcinoma.

Figure 3

Biomarker pipeline. Biomarkers must be carefully evaluated along each phase of the pipeline for successful adoption into clinical practice.