Mechanism of Action

TORISEL is an inhibitor of mTOR

mTOR functions as an important regulator of cell division.1
 
  • The mammalian target of rapamycin (mTOR) is an intracellular protein that has been implicated in multiple growth-related cellular functions2
  • TORISEL is an inhibitor of mTOR
    • —TORISEL binds to an intracellular protein, FKBP-12, and the protein-drug complex inhibits the activity of mTOR that controls cell division3
  • Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells
  • In in vitro studies using renal cell carcinoma cell lines, TORISEL inhibited the activity of mTOR and resulted in reduced levels of hypoxia-inducible factors HIF-1a and HIF-2a and vascular endothelial growth factor (VEGF)4,5
  • The clinical significance of in vitro inhibition is not known
 

The mTOR pathway

mTOR functions as an important regulator of cell division.1
 
UPSTREAM PATHWAY
 
TORISEL INHIBITS mTOR
TORISEL binds to the intracellular protein FKBP-12 and the resulting complex binds to and inhibits mTOR
 
DOWNSTREAM PATHWAY
When mTOR is inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the P13 kinase/AKT pathway is blocked
  • mTOR inhibition results in G1 growth arrest in treated tumor cells
  • mTOR inhibition results in reduced levels of HIF and VEGF in in vitro studies using RCC cell lines4,5
  • The clinical significance of in vitro inhibition is not known
 
REFERENCES
  1. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol. 2003;3(4):371-377.
  2. Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol. 2005;23(23):5386-5403.
  3. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res. 2007;13(11):3109-3114.
  4. Data on file. Pfizer Inc, New York, NY.
  5. Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med. 2006;12(1):122-127.
  6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.3.2015. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed January 13, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.