Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy.

Seraina Faes,Nicolas Demartines,Tania Santoro,Olivier Dormond

doi:10.3390/cancers9110152

Seraina Faes, Nicolas Demartines + Show 2 more

Open Access

https://doi.org/10.3390/cancers9110152

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Journal: Cancers	Publication Date: Nov 1, 2017
Citations: 38	License type: CC BY 4.0

Affiliation: University of Lausanne

Abstract

mTOR inhibitors have demonstrated remarkable anti-tumor activity in experimental models, mainly by reducing cancer cell growth and tumor angiogenesis. Their use in cancer patients as monotherapy has, however, generated only limited benefits, increasing median overall survival by only a few months. Likewise, in other targeted therapies, cancer cells develop resistance mechanisms to overcome mTOR inhibition. Hence, novel therapeutic strategies have to be designed to increase the efficacy of mTOR inhibitors in cancer. In this review, we discuss the present and future relevance of mTOR inhibitors in cancer therapy by focusing on their effects on tumor angiogenesis.

Highlights

The mechanistic target of rapamycin is a serine/threonine kinase that exerts its effect by forming an integral part of two structurally and functionally distinct protein complexes, named mTOR complex 1 and mTOR complex 2 [1,2]. mTORC1 coordinates cell growth in favorable extracellular conditions by stimulating protein, lipid, and nucleotide synthesis, and by inhibiting autophagy [3]. mTORC2 is primarily activated by growth factors, and stimulates cell proliferation and survival by activating members of the group of AGC protein kinases, such as AKT [4,5]
vascular endothelial endothelial growth growth factor factor (VEGF)-mediated endothelial endothelial cell proliferation. It decreased growth mTORC2, in endothelial cells reduced VEGF-mediated cell proliferation. It alsothe decreased of allografts, waswhich associated with diminished tumor angiogenesis roleThe of thetumor growth of tumor which allografts, was associated with diminished tumor angiogenesis mTORC2 in signaling in endothelial cells was further confirmed using a phosphoproteomic role of mTORC2 in VEGF signaling in endothelial cells was further confirmed using a approach
Consistent with this latter hypothesis, it has been shown that treatment of endothelial cells with rapamycin increases the activity of mitogen-activated protein kinase (MAPK), which counteracts the anti-angiogenic efficacy of mTOR inhibitors [42]

Summary

Introduction

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that exerts its effect by forming an integral part of two structurally and functionally distinct protein complexes, named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [1,2]. mTORC1 coordinates cell growth in favorable extracellular conditions by stimulating protein, lipid, and nucleotide synthesis, and by inhibiting autophagy [3]. mTORC2 is primarily activated by growth factors, and stimulates cell proliferation and survival by activating members of the group of AGC protein kinases, such as AKT [4,5]. Decreased cancer cell proliferation reduced tumor angiogenesis are associated frequently with this effect. The effects of kinase inhibitors of mTOR on endothelial cell proliferation, survival, migration, and tube formation have been tested. Reduced vessel density in these models was associated with decreased level of HIF-1 (hypoxia-inducible factor 1) and VEGF, confirming the role of mTOR in hypoxic tumor response. Despite a clear anti-angiogenic activity of mTOR inhibitors in tumor mouse models, few studies have investigated their effects on tumor endothelial cells in vivo. It decreased growth mTORC2, in endothelial cells reduced VEGF-mediated cell proliferation It alsothe decreased of allografts, waswhich associated with diminished tumor angiogenesis [59].

Resistances to the Anti-Angiogenic Effects of mTOR Inhibitors

Biomarkers of Efficacy of mTOR Inhibitors

Conclusions