Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

Br J Cancer. 2009 Apr 21;100(8):1267-76. doi: 10.1038/sj.bjc.6604995. Epub 2009 Mar 24.

Abstract

The phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is frequently deregulated in pancreatic cancers, and is believed to be an important determinant of their biological aggression and drug resistance. NVP-BEZ235 is a novel, dual class I PI3K/mammalian target of rapamycin (mTor) inhibitor undergoing phase I human clinical trials. To simulate clinical testing, the effects of NVP-BEZ235 were studied in five early passage primary pancreatic cancer xenografts, grown orthotopically. These tumours showed activated PKB/Akt, and increased levels of at least one of the receptor tyrosine kinases that are commonly activated in pancreatic cancers. Pharmacodynamic effects were measured following acute single doses, and anticancer effects were determined in separate groups following chronic drug exposure. Acute oral dosing with NVP-BEZ235 strongly suppressed the phosphorylation of PKB/Akt, followed by recovery over 24 h. There was also inhibition of Ser235/236 S6 ribosomal protein and Thr37/46 4E-BP1, consistent with the effects of NVP-BEZ235 as a dual PI3K/mTor inhibitor. Chronic dosing with 45 mg kg(-1) of NVP-BEZ235 was well tolerated, and produced significant tumour growth inhibition in three models. These results predict that agents targeting the PI3K/Akt/mTor pathway might have anticancer activity in pancreatic cancer patients, and support the testing of combination studies involving chemotherapy or other molecular targeted agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / pathology
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Cell Differentiation
  • Child
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Imidazoles / therapeutic use*
  • Immunohistochemistry
  • Mice
  • Mice, SCID
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism
  • Quinolines / therapeutic use*
  • TOR Serine-Threonine Kinases
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • dactolisib