Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

Alberto M. Martelli, Camilla Evangelisti, Francesca Chiarini, Cecilia Grimaldi, Lucia Manzoli, James A. McCubrey

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Background: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. Objective: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. Methods: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. Conclusions: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.

Original languageEnglish
Pages (from-to)1333-1349
Number of pages17
JournalExpert Opinion on Investigational Drugs
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 2009

Fingerprint

Sirolimus
Phosphatidylinositol 3-Kinases
Acute Myeloid Leukemia
Poisons
Growth
Drug Resistance
Pharmaceutical Preparations
Neoplasms
Cell Survival
Stem Cells
Therapeutics
Cell Proliferation
Pharmacology
Safety
Drug Therapy
Survival

Keywords

  • Combination therapy
  • Leukemia
  • Leukemic stem cells
  • PI3K/Akt/mTOR
  • Signal transduction modulators
  • Targeted therapy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Martelli, A. M., Evangelisti, C., Chiarini, F., Grimaldi, C., Manzoli, L., & McCubrey, J. A. (2009). Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. Expert Opinion on Investigational Drugs, 18(9), 1333-1349. https://doi.org/10.1517/14728220903136775

Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. / Martelli, Alberto M.; Evangelisti, Camilla; Chiarini, Francesca; Grimaldi, Cecilia; Manzoli, Lucia; McCubrey, James A.

In: Expert Opinion on Investigational Drugs, Vol. 18, No. 9, 09.2009, p. 1333-1349.

Research output: Contribution to journalArticle

Martelli, AM, Evangelisti, C, Chiarini, F, Grimaldi, C, Manzoli, L & McCubrey, JA 2009, 'Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia', Expert Opinion on Investigational Drugs, vol. 18, no. 9, pp. 1333-1349. https://doi.org/10.1517/14728220903136775
Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Manzoli L, McCubrey JA. Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. Expert Opinion on Investigational Drugs. 2009 Sep;18(9):1333-1349. https://doi.org/10.1517/14728220903136775
Martelli, Alberto M. ; Evangelisti, Camilla ; Chiarini, Francesca ; Grimaldi, Cecilia ; Manzoli, Lucia ; McCubrey, James A. / Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. In: Expert Opinion on Investigational Drugs. 2009 ; Vol. 18, No. 9. pp. 1333-1349.
@article{3641ed9340b24a9d92215c0afc4b55c6,
title = "Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia",
abstract = "Background: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. Objective: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. Methods: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. Conclusions: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.",
keywords = "Combination therapy, Leukemia, Leukemic stem cells, PI3K/Akt/mTOR, Signal transduction modulators, Targeted therapy",
author = "Martelli, {Alberto M.} and Camilla Evangelisti and Francesca Chiarini and Cecilia Grimaldi and Lucia Manzoli and McCubrey, {James A.}",
year = "2009",
month = "9",
doi = "10.1517/14728220903136775",
language = "English",
volume = "18",
pages = "1333--1349",
journal = "Expert Opinion on Investigational Drugs",
issn = "1354-3784",
publisher = "Informa Healthcare",
number = "9",

}

TY - JOUR

T1 - Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

AU - Martelli, Alberto M.

AU - Evangelisti, Camilla

AU - Chiarini, Francesca

AU - Grimaldi, Cecilia

AU - Manzoli, Lucia

AU - McCubrey, James A.

PY - 2009/9

Y1 - 2009/9

N2 - Background: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. Objective: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. Methods: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. Conclusions: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.

AB - Background: The PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in cell growth, proliferation and survival not only under physiological conditions but also in a variety of tumor cells. Therefore, the PI3K/Akt/mTOR axis may be a critical target for cancer therapy. Objective: This review discusses how PI3K/Akt/mTOR signaling network is constitutively active in acute myelogenous leukemia (AML), where it strongly influences proliferation, survival and drug-resistance of leukemic cells, and how effective targeting of this pathway with pharmacological inhibitors, used alone or in combination with existing drugs, may result in suppression of leukemic cell growth, including leukemic stem cells. Methods: We searched the literature for articles dealing with activation of this pathway in AML and highlighting the efficacy of small molecules directed against the PI3K/Akt/mTOR signaling cascade. Conclusions: The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.

KW - Combination therapy

KW - Leukemia

KW - Leukemic stem cells

KW - PI3K/Akt/mTOR

KW - Signal transduction modulators

KW - Targeted therapy

UR - http://www.scopus.com/inward/record.url?scp=68849130702&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68849130702&partnerID=8YFLogxK

U2 - 10.1517/14728220903136775

DO - 10.1517/14728220903136775

M3 - Article

C2 - 19678801

AN - SCOPUS:68849130702

VL - 18

SP - 1333

EP - 1349

JO - Expert Opinion on Investigational Drugs

JF - Expert Opinion on Investigational Drugs

SN - 1354-3784

IS - 9

ER -