The metabolic and toxicological considerations for mTOR inhibitors in the treatment of hepatocarcinoma.
BACKGROUND
Hepatocellular carcinoma (HCC) is a major health problem worldwide. Several molecular pathways involved in HCC growth and progression have recently been identified. Rapamycin analogs are able to inhibit one of the most active oncogenic molecular pathways in HCC cells: the mammalian target of rapamycin (mTOR) pathway.


METHODS
In this review, the authors analyze the principal molecular features of the mTOR pathway and the use of rapamycin analogs in the treatment of hepatocarcinoma. The article also looks at the reoccurrence of HCC following liver transplantation as well as after the treatment of de novo neoplasms. Finally, the authors discuss the advantage of using a combined HCC pharmacological therapy to obtain a synergistic effect on tumor mass.


CONCLUSIONS
Among the available options for the treatment of advanced-stage HCC, mTOR pathway inhibitors show great promise. Once these agents have their safety and efficacy confirmed, in the treatment of liver disease, their use should be considered in patients affected by HCC. This should especially be the case for those who have had liver transplants or suffered with de novo tumors. Moreover, the authors believe that mTOR inhibitors could be used in a combined pharmacological approach to improve HCC molecular-targeted therapy by producing a multiple-level block of tumor intracellular signaling.
Catholic University of Sacred Heart, Gemelli Hospital, Largo A. Gemelli, 8 Rome 00168, Italy.
Francesca
F
Ponziani
Veronica
V
Ojetti
Annalisa
A
Tortora
Luca
L
Di Maurizio
Flaminia
F
Purchiaroni
Antonio
A
Gasbarrini
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016031:Liver Transplantation; D058990:Molecular Targeted Therapy / Q000379:methods; D009367:Neoplasm Staging; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus