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Open Access Review

Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment

Irene Brana and Lillian L Siu*

Author Affiliations

Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada

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BMC Medicine 2012, 10:161  doi:10.1186/1741-7015-10-161

Published: 11 December 2012

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.

Keywords:
PI3K; isoform; neoplasm; patient selection; clinical trials; cancer