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Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations.

Publication ,  Journal Article
LoPiccolo, J; Blumenthal, GM; Bernstein, WB; Dennis, PA
Published in: Drug Resist Updat
2008

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection.

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Published In

Drug Resist Updat

DOI

EISSN

1532-2084

Publication Date

2008

Volume

11

Issue

1-2

Start / End Page

32 / 50

Location

Scotland

Related Subject Headings

  • Treatment Outcome
  • TOR Serine-Threonine Kinases
  • Substrate Specificity
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Protein Kinases
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasms
  • Humans
 

Citation

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LoPiccolo, J., Blumenthal, G. M., Bernstein, W. B., & Dennis, P. A. (2008). Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat, 11(1–2), 32–50. https://doi.org/10.1016/j.drup.2007.11.003
LoPiccolo, Jaclyn, Gideon M. Blumenthal, Wendy B. Bernstein, and Phillip A. Dennis. “Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations.Drug Resist Updat 11, no. 1–2 (2008): 32–50. https://doi.org/10.1016/j.drup.2007.11.003.
LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008;11(1–2):32–50.
LoPiccolo, Jaclyn, et al. “Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations.Drug Resist Updat, vol. 11, no. 1–2, 2008, pp. 32–50. Pubmed, doi:10.1016/j.drup.2007.11.003.
LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008;11(1–2):32–50.
Journal cover image

Published In

Drug Resist Updat

DOI

EISSN

1532-2084

Publication Date

2008

Volume

11

Issue

1-2

Start / End Page

32 / 50

Location

Scotland

Related Subject Headings

  • Treatment Outcome
  • TOR Serine-Threonine Kinases
  • Substrate Specificity
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Protein Kinases
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasms
  • Humans