Exploitation of Aberrant Signalling Pathways as Useful Targets for Renal Clear Cell Carcinoma Therapy

Abstract

Renal cell carcinoma (RCC) is the third leading cause of death among urological tumours, annually afflicts about 150, 000 people globally and causes nearly 78, 000 deaths (Jemal et al., 2008; Zbar et al., 2003). RCC is an epithelial tumour consisting of several different histological subtypes of which clear cell RCC is the prototypical. Traditionally treatment has been via surgery and immunotherapy. Surgical resection is appropriate for some patient cohorts including those with isolated metastases. However, recurrence is common even when the primary and metastatic sites have been aggressively resected (Couillard & deVere White, 1993). RCC is highly unresponsive to standard chemotherapy and the use of cytokine therapy with interleukin (IL)-2 or interferon (IFN)-┙ is associated with low rates of response and high rates of toxicity (Oudard et al., 2007). Thus, development of new therapies continues to be crucial to improve outcomes in patients with RCC. The increased understanding of the molecular structure and aberrant activity of signalling pathways in RCC has lead to a flurry of research activity in the arena of targeted therapies namely anti-angiogenic vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR), both of which are involved in the pathogenesis of RCC (Mulders, 2009). These advancements in an obvious therapeutic gap have significantly improved the progression free survival (PFS) of patients with RCC. Despite the explosion in drug development during the past five years, however, PFS for patients with metastatic RCC (mRCC) still remains poor as none of the current targeted therapies possess the capacity to induce remission. In addition these drugs provide dose-limiting toxic side effects and so we are still faced with a considerable task in developing newer safer therapeutics for use as either first line agents or in combination with existing ones.