PI3K/AKT inhibitors in patients with refractory renal cell carcinoma: what have we learnt so far?

<span class="paragraphSection">A better understanding of the pathophysiology of renal cell carcinoma (RCC) on a molecular level has led to the development of new treatment strategies. The discovery of the von Hippel-Lindau (<span style="font-style:italic;">VHL)</span> gene and its role in regulating pro-angiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor and others, have led to the development of targeted therapies. Multi-tyrosine kinase inhibitors (e.g. sunitinib, sorafenib, pazopanib, axitinib, cabozantinib and lenvatinib), the VEGF-A ligand antibody (bevacizumab) that blocks the VEGF pathway, as well as the mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) that block the mTOR pathway have emerged as powerful clinical tools in the management of advanced disease. These agents have been approved by the FDA based on a series of pivotal phase II and III trials demonstrating efficacy in improving objective response rates and progression-free survival (PFS) [<a href="#mdx104-B1" class="reflinks">1</a>]. However, despite the fact that these therapies have dramatically changed the outcome of patients with advanced RCC, complete remissions remain extremely rare and the median time to disease progression is roughly 8–11 months, and shorter if the patient's characteristics include adverse clinical features. The development of resistance eventually occurs during the course of the disease, resulting in poor outcomes [<a href="#mdx104-B2" class="reflinks">2–5</a>].</span>

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