Targeting the PI3K/AKT/mTOR pathway in non-Hodgkin's lymphoma: Results, biology, and development strategies

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Abstract

Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in non-Hodgkin's lymphoma (NHL), prompting evaluation of the rapamycin-analog (rapalog) mTOR inhibitors in multiple clinical trials. The drugs show activity as single agents, and the rapalog temsirolimus is now accepted as a therapeutic option in relapsed/refractory mantle cell lymphoma. Response rates, however, are typically below 50%, resulting in remissions that are neither complete nor durable. Results of preclinical studies shed important new light on resistance mechanisms that may explain results. Looking ahead, it is likely PI3K/AKT/ mTOR inhibition will find expanded roles in NHL therapy due to 1) assessments of the rapalogs in combination with other therapies and in less heavily pretreated patients, 2) the development and evaluation of multiple novel inhibitors of the pathway that may increase specificity and potency, 3) alternative treatment strategies able to bypass particular resistance mechanisms, and 4) increased efforts to identify biomarkers for better pretreatment patient stratification.

Original languageEnglish (US)
Pages (from-to)398-406
Number of pages9
JournalCurrent Oncology Reports
Volume13
Issue number5
DOIs
StatePublished - Oct 2011
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Non-Hodgkin's Lymphoma
Sirolimus
Mantle-Cell Lymphoma
Therapeutics
Biomarkers
Clinical Trials
Pharmaceutical Preparations

Keywords

  • 4E-BP1
  • eIF4E
  • mTOR inhibitors
  • Non-Hodgkin's lymphoma
  • PI3K/AKT/mTOR pathway
  • PIM family kinases .MNK kinases
  • Signal transduction
  • Targeted cancer therapeutics
  • Translation initiation

ASJC Scopus subject areas

  • Oncology

Cite this

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abstract = "Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in non-Hodgkin's lymphoma (NHL), prompting evaluation of the rapamycin-analog (rapalog) mTOR inhibitors in multiple clinical trials. The drugs show activity as single agents, and the rapalog temsirolimus is now accepted as a therapeutic option in relapsed/refractory mantle cell lymphoma. Response rates, however, are typically below 50{\%}, resulting in remissions that are neither complete nor durable. Results of preclinical studies shed important new light on resistance mechanisms that may explain results. Looking ahead, it is likely PI3K/AKT/ mTOR inhibition will find expanded roles in NHL therapy due to 1) assessments of the rapalogs in combination with other therapies and in less heavily pretreated patients, 2) the development and evaluation of multiple novel inhibitors of the pathway that may increase specificity and potency, 3) alternative treatment strategies able to bypass particular resistance mechanisms, and 4) increased efforts to identify biomarkers for better pretreatment patient stratification.",
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