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Genotype directed therapy in murine mismatch repair deficient tumors

Melanie H Kucherlapati1, Shadi Esfahani, Peiman Habibollahi

  • 1Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.

Plos One
|August 13, 2013
PubMed

Insights

Dual PI3K/mTOR inhibitor NVP-BEZ235, with or without MEK inhibitor ADZ4266, reduced intestinal tumors in Msh2 mouse models. Some resistant tumors persisted, indicating potential for new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is frequently activated in human cancers.
  • Wnt signaling dysfunction and PI3K/AKT/mTOR pathway upregulation are observed in Msh2(-/-) mouse-initiated intestinal tumors.

Purpose of the Study:

  • To evaluate the efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, alone and in combination with MEK inhibitor ADZ4266, in treating Msh2-deficient intestinal tumors.
  • To investigate the molecular alterations and resistance mechanisms in treated tumors.

Main Methods:

  • Treatment of two Msh2 mouse models with intestinal tumors using NVP-BEZ235 and/or ADZ4266.
  • Disease monitoring via pathology, 18F-FDG PET imaging, and endoscopy.
  • Analysis of key pathway proteins including PTEN, AKT, MEK, MAPK, S6K, mTOR, PDPK1, and Cyclin D1.

Main Results:

  • Both drug regimens significantly decreased intestinal adenocarcinoma multiplicity.
  • Combined therapy led to significant regression in most tumors, but a subset of highly progressed tumors persisted.
  • Variable molecular alterations were observed, including PTEN downregulation, AKT and downstream signaling upregulation, and intact or absent apoptosis in different tumors.

Conclusions:

  • NVP-BEZ235, alone and combined with ADZ4266, shows efficacy in a proportion of colorectal cancers.
  • Highly progressed, resistant tumors can still grow under treatment, suggesting the need for alternative therapeutic strategies.
  • Upregulation of pathways like PDPK1 in resistant tumors suggests potential utility of metabolic inhibitors.

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