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Target of rapamycin signaling in leukemia and lymphoma

Collin Vu1, David A Fruman

  • 1Division of Hematology/Oncology, Department of Medicine, University of California-Irvine, CA 92697, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 10, 2010
PubMed

Insights

New active-site TOR inhibitors (asTORi) show greater efficacy and tolerability than rapalogs for treating blood cancers like leukemia and lymphoma by broadly suppressing the PI3K/AKT/TOR pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K)/AKT/TOR signaling pathway is crucial in various human cancers, particularly hematologic malignancies.
  • Targeting the target of rapamycin (TOR) kinase is a therapeutic strategy for leukemia, lymphoma, and myeloma.
  • Current TOR inhibitors, rapalogs, only partially inhibit TORC1 and do not acutely inhibit TORC2.

Purpose of the Study:

  • To discuss strategies for inhibiting TOR in hematologic malignancies.
  • To compare the efficacy and tolerability of active-site TOR inhibitors (asTORi) with rapalogs.

Main Methods:

  • Review of preclinical and clinical strategies targeting TOR.
  • Comparison of rapalogs and active-site TOR inhibitors (asTORi) in preclinical models.
  • Evaluation of PI3K/AKT/TOR signaling network suppression.

Main Results:

  • Active-site TOR inhibitors (asTORi) achieve greater inhibition of both TORC1 and TORC2 complexes.
  • asTORi demonstrate greater efficacy than rapalogs in Philadelphia chromosome-positive acute lymphoblastic leukemia and T-cell lymphoma.
  • asTORi exhibit improved tolerability in animal models compared to rapalogs or PI3K inhibitors.

Conclusions:

  • Active-site TOR inhibitors represent a promising new class of drugs for hematologic malignancies.
  • Broader evaluation of asTORi is warranted in acute myeloid leukemia, B-cell lymphoma, myeloma, and other blood cancers.
  • asTORi offer a potential therapeutic advantage over existing rapalogs due to enhanced efficacy and tolerability.

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