The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer.
Inhibitors of the mammalian target of rapamycin (mTOR) have shown promising efficacy in early-stage trials in patients with advanced renal cell carcinoma (RCC). Most RCCs have been shown to possess biallelic alterations in the von Hippel-Lindau (VHL) gene, resulting in accumulation of hypoxia-inducible factors 1alpha and 2alpha, as well as their downstream targets including vascular endothelial growth factor (VEGF). The observed clinical efficacy of mTOR inhibitors in patients with RCC may be mediated in part by the dependence of efficient hypoxia-inducible factor translation on the mTOR pathway. mTOR inhibitors have entered more advanced phase clinical trials either as single agents or in combination with other targeted agents or IFN, which might ultimately result in regulatory approval of one or more agents. Given the likely nonoverlapping mechanism of action of mTOR inhibitors and VEGF pathway-targeted agents, mTOR inhibitors may prove useful if administered in combination or after resistance to VEGF inhibitors. With an increasing number of active agents for treatment of patients with RCC, efforts must continue to develop patient selection models based on predictive biomarkers to direct therapy to appropriate patients.
Cho
Daniel
D
Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Signoretti
Sabina
S
Regan
Meredith
M
Mier
James W
JW
Atkins
Michael B
MB
D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000628:therapy*; D002986:Clinical Trials as Topic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007372:Interferons / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000628:therapy*; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D007372:Interferons; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus