The biology behind mTOR inhibition in sarcoma.
Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target for anticancer drug development. Currently, the mTOR inhibitor rapamycin and its derivatives CCI-779, RAD001, and AP23573 are being evaluated in cancer clinical trials. To date, clinical results have shown good tolerability of treatment with mTOR inhibitors in most reports and varying effectiveness of mTOR inhibitors in a variety of tumors in a subset of patients. For the targeted treatment of sarcomas, AP23573 has shown promising clinical efficacy and low toxicity profiles in patients. Further studies should define the optimal dose/schedule, patient selection, and combination strategies with other biological agents, especially those targeting signaling pathways crucial for cell survival. Disclosure of potential conflicts of interest is found at the end of this article.
Wan
Xiaolin
X
Molecular Oncology Section, Pediatric Oncology Branch, Building 10, Room CRC-1W-3816, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1928, USA.
Helman
Lee J
LJ
D002986:Clinical Trials as Topic; D000068338:Everolimus; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C515074:ridaforolimus; C401859:temsirolimus; C546842:MTOR protein, human