ESMO E-Learning: mTOR Inhibition/Targeting in Solid Tumours

Learning Objectives

  • To understand signalling pathway defects in specific solid tumours that may result in mTOR activation and therefore offer a rationale for the clinical use of mTOR inhibitors.
  • To understand mechanism of action of mTOR inhibitors and implications on the design of clinical studies, as well as a need for valid biomarkers.
  • To understand the toxicity profiles of mTOR inhibitor.
Jaap Verweij
Jaap Verweij
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Stefan Sleijfer
Stefan Sleijfer
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The mammalian target of the rapamycin (mTOR) protein complex functions as an integration centre for various intracellular signalling pathways. The activated mTOR pathway plays a role in the regulation of cell proliferation, cell survival, Angiogenesis, and resistance to antitumour treatments. In many solid tumours this pathway has been found activated through several different underlying mechanisms.

Because of its frequent dysregulation, mTOR inhibition is considered as a potentially important antitumour target. Currently, four mTOR inhibitors are being explored for clinical use: rapamycin, temsirolimus, everolimus, and ridaforolimus. As monotherapy, mTOR inhibitors yield interesting antitumour activity against various tumour types with relatively mild toxicities. This recently resulted in the registration of two mTOR inhibitors for use in patients with metastatic renal cell cancer, giant-cell astrocytomas associated with tuberous sclerosis, pancreatic neuroendocrine tumours, and astrocytoma associated with tuberous sclerosis, while randomised studies in other solid tumours are currently underway.

It has also been determined that in preclinical models mTOR inhibition overcomes chemoresistance, therefore mTOR inhibitors have been considered to be suitable for combining with other antitumour drugs. Consequently, multidrug regimens containing mTOR inhibitors are being investigated in clinical trials. Identification of patients who are likely to respond to mTOR inhibition is of utmost importance and preliminary research results suggest that several factors reflecting activation of mTOR in tumours may be used for this purpose.

This E-Learning module addresses the mechanism of action and current clinical experience with mTOR inhibitors, as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of treatment outcome to mTOR inhibition are discussed.

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This E-Learning module was published in 2011 and expired in 2013.

Last update: 21 October 2011

Prof. Sleijfer has reported to be currently conducting an investigator-initiated study with an unrestricted research grant from Novartis. Prof. Verweij has reported no conflict of interest.