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Current development of mTOR inhibitors as anticancer agents

Key Points

  • Mammalian target of rapamycin (mTOR) is a key kinase that acts as a master switch of cellular catabolism, anabolism, proliferation, cell-cycle control, autophagy, angiogenesis and apoptosis. Human malignancies display a plethora of molecular abnormalities involving phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and/or the PI3K/AKT/mTOR pathway.

  • Rapamycin, a potent mTOR inhibitor, was initially developed as an immunosuppressive agent that, unlike cyclosporine, decreases the risk of post-transplant lymphoproliferative disorders. Both rapamycin itself and rapamycin derivatives (CCI-779, RAD001 and AP23573) have demonstrated antiproliferative and antitumour effects in preclinical models and clinical malignancies.

  • CCI-779 when given weekly as a single agent was the first-in-class mTOR inhibitor to demonstrate survival improvement as compared with interferon in patients with poor-prognosis advanced renal cell carcinoma.

  • Translational studies performed during clinical trials identified molecular markers — p-S6K1 and p-4EBP1 — that were used to monitor biological effects of mTOR inhibitors.

  • Resistance to rapamycin derivatives might result from a lack of AKT activation and/or deficient apoptosis pathways (such as BCL2 expression), and useful biomarkers to predict such therapeutic responses are yet to be discovered.

  • Multitargeting approaches combining other targeted therapy, hormone therapy and/or chemotherapy might improve the therapeutic potential of mTOR derivatives.

Abstract

Mammalian target of rapamycin (mTOR) is a kinase that functions as a master switch between catabolic and anabolic metabolism and as such is a target for the design of anticancer agents. The most established mTOR inhibitors — rapamycin and its derivatives — showed long-lasting objective tumour responses in clinical trials, with CCI-779 being a first-in-class mTOR inhibitor that improved the survival of patients with advanced renal cell carcinoma. This heralded the beginning of extensive clinical programmes to further evaluate mTOR inhibitors in several tumour types. Here we review the clinical development of this drug class and look at future prospects for incorporating these agents into multitarget or multimodality strategies against cancer.

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Figure 1: Dysregulation of the PI3K/AKT/mTOR signalling pathway in human cancer.
Figure 2: Effect of mTOR inhibitors on cancer cells.
Figure 3: The effect of modulation of the PI3K/AKT/mTOR pathway with rapamycin derivatives on endothelial and tumour cells.
Figure 4: Antitumour effects of mTOR inhibitors in patients with cancer.
Figure 5: Bench-to-bedside translational research using molecular markers to assess biologically active doses of mTOR inhibitors.
Figure 6: Complexity of the multitargeted approach to cancer therapy.

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DATABASES

OMIM

Cowden syndrome

Glossary

Receptor tyrosine kinases

(RTKs). A family of transmembrane receptors that are physiologically activated by the extracellular binding of growth factor(s) and which initiate intracellular signalling, ultimately leading to many cellular responses such as proliferation. Abnormalities of these receptors are often reported in human malignancies.

Translational research

Research aimed at using biological tools for clinical applications.

Glioblastoma

High-grade brain malignancy arising from astrocytes with abnormal cellular proliferation and increased tumour angiogenesis. This cancer is usually refractory to chemotherapy and has a very poor prognosis.

Mucositis

Inflammation and/or ulceration of mouth mucosa.

Thrombocytopaenia

Low level of platelets in circulating blood.

Objective response

Shrinkage of at least 50% of malignant target lesions (according to World Health Organization criteria) after administration of anticancer treatment as compared with baseline measurement.

Sarcoma

Malignant tumour arising from the bone (osteosarcoma) or the soft tissues with high risk of lung metastasis. Patients with soft tissue sarcomas are frequently poor responders to classical chemotherapy.

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Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5, 671–688 (2006). https://doi.org/10.1038/nrd2062

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