mTOR inhibitors for hepatocellular cancer: a forward-moving target.
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.
Treiber
Gerhard
G
Department of Internal Medicine, Zollernalb Clinic, Academic Teaching Hospital of Tuebingen University, Balingen, Germany. gt@helico.de
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D004357:Drug Synergism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D016031:Liver Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases