mTOR inhibitors for hepatocellular cancer: a forward-moving target

Abstract

mTOR is a central regulator of cell growth and angiogenesis. The mTOR pathway is activated in 40–50% of patients with hepatocellular cancer (HCC). In different models (i.e., hepatoma cell lines and implanted HCC tumors in rats), mTOR inhibitors (mTORIs) were effective in reducing cell growth and tumor vascularity. Synergistic effects were observed for mTORIs and chemotherapeutic agents in these studies, while other combinations involving mTORIs and inhibitors of growth hormones and angiogenesis are awaiting further clinical testing. A number of mTORIs are already clinically available (e.g., sirolimus, temsirolimus and everolimus), sharing similiar pharmacokinetic parameters (except for absorption) and side effects. Clinical data are, as yet, only preliminary and are mainly derived from retrospective studies in patients who underwent liver transplantation for HCC. Those patients had received sirolimus thereafter for immunosuppression, and a much lower rate of tumor recurrence than with calcineurin inhibitors alone was noted. Current prospective trials for treatment of advanced HCC include mTORIs alone or in combination with either transarterial chemoembolization or other systemic drugs, and will be discussed in detail in this review.

Keywords::

• everolimus
• hepatocellular cancer
• inhibitor
• mammalian target of rapamycin
• sirolimus
• temsirolimus

Financial & competing interests disclosure

The author has received research grants/consultancy fees from Novartis Oncology in the context of this review. Additional aspects on the topic of this review have been presented during the Monothematic Conference of European Association for the Study of the Liver (EASL), held at Prague, Czech Republic, 12–14 June 2008: Liver Cancer – From Molecular Pathogenesis to New Therapies. These can be accessed via www.easl.ch. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.