Use of APO2L/TRAIL with mTOR inhibitors in the treatment of glioblastoma multiforme.
The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation and survival. Components of the mTOR pathway are activated in a variety of tumors, including glioblastoma multiforme (GBM), and we have found that one surprising consequence of mTOR pathway activation is resistance of GBMs to the proapoptotic effects of agents such as APO2L/TRAIL. mTOR inhibition has become feasible following the development of rapamycin and comparable analogs with improved pharmacological properties, including CCI-779, RAD001 and AP23573. Numerous studies have also demonstrated promising proapoptotic activity, with relatively mild side effects, using rapamycin analogs in vitro and in vivo in conjunction with APO2L/TRAIL. These studies suggest that mTOR inhibitors can be combined with APO2L/TRAIL as a potential tumor-selective therapy.
Panner
Amith
A
Brain Tumor Research Center, Department of Neurological Surgery and the Comprehensive Cancer Center, University of California, San Francisco, CA 94143-0875, USA. apanner@cc.ucsf.edu
Parsa
Andrew T
AT
Pieper
Russell O
RO
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus