Highlights of This Issue

Successful development of targeted therapeutics now and in the future will hinge on defining patient subsets that are most likely to benefit from new drug candidates. Walter and colleagues combined microfluidics-based gene expression analysis and genome-wide methylation profiling to determine if DNA methylation patterns could classify clinically relevant phenotypic subsets of non–small cell lung cancer (NSCLC). DNA methylation patterns divided NSCLC cell lines and tumors into epithelial-like and mesenchymal-like subtypes. These findings show that DNA methylation profiles can serve as surrogates for gene expression profiles and provide proof-of-principle that DNA methylation differences can be used as a platform for predictive biomarker discovery and development.

Overexpression of Auroras is implicated in oncogenic transformation associated with chromosomal instability in human malignancy. In mantle cell lymphoma, Aurora A and B are prognostic markers and therapeutic targets. To investigate Auroras as therapeutic targets, Mahadevan and colleagues evaluated the synergistic combination of MLN8237 with vincristine (MV) in a mouse xenograft model of mantle cell lymphoma and observed that the combination led to tumor regression. However, the tumors returned 2 weeks after treatment. Addition of rituximab to MV resulted in tumor regression and cure, with no relapses 120 days after treatment. Hence, rituximab has synthetic lethality with the MV regimen. A phase I/II study is evaluating MV combined with rituximab in relapsed refractory B-cell lymphoma.

The dual-targeting strategy involving phosphoinositide 3-kinase/AKT and RAS/MEK pathways in cancer treatment is particularly intriguing because there is evidence that both pathways are extensively interconnected. Shimizu and colleagues found, through an analysis from a phase I database, that dual inhibition of both pathways may show favorable efficacy compared with single inhibition of either pathway alone, at the expense of greater toxicity in a clinical setting. They also report potentially promising clinical benefits in patients who were treated with combination drug regimens simultaneously targeted to both pathways. These data could provide a platform for further in-depth investigation of molecular profiling and matching of patients with combinations of these targeted drugs for personalized treatment.

Diagnostic evaluation of advanced non–small cell lung cancer (NSCLC) could be aided considerably by robust circulating biomarkers. Punnoose and colleagues showed that evaluation of circulating tumor cells (CTC) and circulating tumor DNA can provide information about the molecular characteristics of a patient's tumor from a noninvasive blood draw. They found that mutational analysis of cell-free DNA from blood was more sensitive than analyses of captured CTCs for determining the epidermal growth factor receptor genotype. Moreover, decreases in CTC numbers during treatment of advanced NSCLC patients with targeted therapies were associated with antitumor activity based on imaging endpoints and progression-free survival.