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Nat Rev Clin Oncol. 2013 Mar;10(3):143-53. doi: 10.1038/nrclinonc.2013.10. Epub 2013 Feb 12.

Development of PI3K inhibitors: lessons learned from early clinical trials.

Author information

1
Medical Oncology Department, Vall d'Hebrón University Hospital, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119, Edifici Maternoinfantil Planta 14, 08035 Barcelona, Spain. jrodon@vhio.net

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents--whether observed sequelae could be mechanism-based or off-target effects--and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.

PMID:
23400000
DOI:
10.1038/nrclinonc.2013.10
[Indexed for MEDLINE]

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