Non-Clear Cell Renal Cancer: Disease-Based Management and Opportunities for Targeted Therapeutic Approaches

A better understanding of the biology of renal cell carcinoma (RCC) has significantly changed the treatment paradigm of the disease. Several novel vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been approved recently by the US Food and Drug Administration. Unfortunately, the vast majority of clinical trials conducted today have been aimed to include patients with clear cell RCC, which remains the most common histologic subtype of the disease. Non-clear cell RCC represents approximately 20%-25% of all RCC patients. Non-clear cell RCC is made up of multiple histologic subtypes, each with a different molecular printing profile. Although VEGF and TORC inhibitors are commonly used in the management of this cohort of patients, non-clear cell histologies do not appear to be related to the von Hippel-Lindau gene (VHL). As such, the clinical efficacy of the existing agents is quite limited. There is a need to develop more rational therapeutic approaches that specifically target the biology of each of the different subtypes of non-clear cell RCC. In this review, we discuss molecular and clinical characteristics of each of the non-clear cell RCC subtypes and describe ongoing efforts to develop novel agents for this subset of patients.