mTOR-blocking agents in advanced renal cancer: an emerging therapeutic option.
BACKGROUND
The mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-alpha.


OBJECTIVE
The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development.


METHODS
The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs.


CONCLUSIONS
Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.
Dasanu
Constantin A
CA
Saint Francis Hospital and Medical Center, Hematology and Medical Oncology, Gothic Park, 43 Woodland Street, Hartford, CT 06105, USA. c_dasanu@yahoo.com
Clark
Bernard A
BA
Alexandrescu
Doru T
DT
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D017674:Hypophosphatemia / Q000139:chemically induced; D007680:Kidney Neoplasms / Q000188:drug therapy*; D011494:Protein Kinases / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus