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PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML

S Park1, N Chapuis, V Bardet

  • 1Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.

Leukemia
|June 13, 2008
PubMed

Insights

The novel drug PI-103 effectively targets both PI3K/Akt and mTOR pathways, crucial in acute myelogenous leukemia (AML). This dual inhibition shows promise for AML therapy by reducing leukemic cell growth and inducing apoptosis, sparing normal cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently hyperactivated in acute myelogenous leukemia (AML).
  • Inhibition of mTORC1 alone can lead to compensatory activation of the PI3K/Akt pathway, suggesting a need for dual inhibition strategies.
  • Existing therapies targeting individual components of these pathways have shown limitations in effectively treating AML.

Purpose of the Study:

  • To evaluate the efficacy of PI-103, a novel dual inhibitor of PI3K/Akt and mTOR, in preclinical models of AML.
  • To assess the impact of PI-103 on leukemic cell proliferation, apoptosis, and stem cell compartments.
  • To determine the safety profile of PI-103 in normal hematopoietic stem cells.

Main Methods:

  • Treatment of human AML cell lines and primary AML patient cells with PI-103.
  • Assessment of PI3K/Akt and mTORC1 signaling pathway activation.
  • Cell cycle analysis, proliferation assays, clonogenicity assays, and apoptosis assays (including mitochondrial apoptosis).
  • Evaluation of PI-103 effects on normal CD34(+) cells.

Main Results:

  • PI-103 effectively inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation in AML cells.
  • PI-103 demonstrated cytostatic effects, induced G1 cell cycle arrest in cell lines, and inhibited proliferation and clonogenicity in primary AML cells.
  • PI-103 induced mitochondrial apoptosis, particularly in leukemic stem cells, without significant toxicity to normal CD34(+) cells.
  • Combination therapy with etoposide showed additive proapoptotic effects.

Conclusions:

  • Dual inhibition of PI3K/Akt and mTOR pathways with PI-103 is a promising therapeutic strategy for AML.
  • PI-103 exhibits potent anti-leukemic activity by targeting key signaling pathways and leukemic stem cells.
  • PI-103 demonstrates a favorable therapeutic window, with minimal impact on normal hematopoietic stem cells, suggesting its potential clinical utility in AML treatment.

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