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Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice

J M García-Martínez1, S Wullschleger, G Preston

  • 1MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

British Journal of Cancer
|March 17, 2011
PubMed
Abstract

Insights

Specific PI3K-mTOR pathway inhibitors AZD8055 and GDC-0941 showed significant tumor volume reduction in a B-cell lymphoma mouse model. However, these kinase inhibitors did not achieve complete tumor regression when used alone.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase-mammalian target of rapamycin (PI3K-mTOR) pathway is frequently activated in various cancers.
  • Targeting this pathway with kinase inhibitors is a promising therapeutic strategy for cancer treatment.
  • PTEN(+/-)LKB1(+/hypo) mice spontaneously develop B-cell follicular lymphoma, providing a relevant model for studying pathway inhibitors.

Purpose of the Study:

  • To evaluate the efficacy of specific mTOR (AZD8055) and PI3K (GDC-0941) inhibitors in a spontaneous B-cell follicular lymphoma mouse model.
  • To assess the impact of these inhibitors on tumor volume, cellular proliferation, apoptosis, and key signaling pathways.

Main Methods:

  • Administration of AZD8055 or GDC-0941 to PTEN(+/-)LKB1(+/hypo) mice with B-cell follicular lymphoma.
  • Tumor volume measurement using Magnetic Resonance Imaging (MRI).
  • Immunohistochemistry, immunoblotting, and flow cytometry were used for sample analysis.

Main Results:

  • AZD8055 and GDC-0941 induced approximately 40% tumor volume reduction within two weeks.
  • Inhibitor treatment led to decreased phosphorylation of AKT, S6K, and SGK, reduced proliferation, increased apoptosis, and suppressed the centroblast population.
  • Extended treatment (6 weeks) resulted in a moderate additional decrease (approx. 50%), but tumors regrew upon cessation of treatment.

Conclusions:

  • Specific PI3K and mTOR inhibitors demonstrate effectiveness in a spontaneous tumor model, potentially more representative than xenografts.
  • These kinase inhibitors show promise for treating cancers with activated PI3K pathway.
  • Monotherapy with these inhibitors may not lead to complete tumor regression, suggesting combination strategies might be necessary.

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