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.
Overview
- The study focuses on the phosphatidylinositol 3-kinase (PI3K) pathway, which is commonly deregulated in cancer. The study aims to analyze the results of the first phase I clinical trials with PI3K inhibitors and propose strategies to optimize the clinical development of these drugs. The main focus of the study is on PI3K isoform-specific inhibitors, which are described in detail, including their functions, preclinical activity, and early clinical data.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions, specifically comparing the number of objective responses to PI3K inhibitors with other targeted agents such as BRAF inhibitors in melanoma or crizotinib in ALK translocated tumors. The study finds that the number of objective responses to PI3K inhibitors is less dramatic compared to other targeted agents. However, the study proposes possible strategies to optimize the clinical development of PI3K inhibitors, including exploring the potential role of PI3K isoform-specific inhibitors, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance.
Implications and Future Directions
- The study's findings suggest that PI3K isoform-specific inhibitors have the potential to improve the therapeutic index of these drugs. The study proposes that molecular characterization as a basis for patient selection and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance should be further explored in future research. The study also suggests that selective PI3K isoform-specific inhibitors should be further developed and tested in clinical trials to determine their efficacy and safety in cancer treatment.