Highlights of This Issue Free

KU-60019 is a novel and specific ATM kinase inhibitor that blocks the radiation-induced DNA damage response and potently radiosensitizes human glioma cells. To see whether KU-60019 would be an effective radiosensitizer in vivo, Biddlestone-Thorpe and colleagues utilized orthotopic human glioma xenograft models varying in p53 status and invasiveness. They show, for the first time, that an ATM kinase inhibitor significantly increases the survival of irradiated mice. Importantly, mutant p53 glioma was much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Thus, an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.

Navarro and colleagues analyzed the expression profiling of 664 microRNAs (miRNA) in mantle cell lymphoma (MCL) to identify biomarkers involved in the pathogenesis of the disease and clinically relevant subtypes. The differential miRNA expression profile identified 2 subgroups of the disease that differ in clinical and biologic characteristics. These miRNAs regulate relevant pathways in the pathogenesis of MCL, including DNA stress response, CD40 signaling, and chromatin modification. miR-34a was identified and validated as a new prognostic marker in MCL in cooperation with MYC overexpression.

Notch pathway inhibitors are being investigated as targeted therapies in a wide range of cancers and can modulate signaling cascades regulating differentiation, survival, and growth. Chu and colleagues tested the effects of an oral γ-secretase inhibitor in xenografts generated from glioblastoma stem cells and identified suppression of clonogenicity and in vivo growth capacity that persisted long after treatment stopped. Their data provide further support for the use of γ- secretase inhibitors in treating malignant brain tumors and suggest that Notch blockade can have both acute and long-term effects on tumor biology.

This cohort study and integrated analysis of data from 17 previous reports defines the characteristics of PIK3CA- and PTEN-mutated colorectal cancers. Day and colleagues show that phosphoinositide 3-kinase (PI3K) pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-high/CIMP-high/BRAF mutation) and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the so-called traditional serrated pathway of tumorigenesis (CIMP-low/KRAS mutation). Mutation status did not predict relapse in stage II/III colorectal cancer. These data highlight the PI3K pathway as a preferential therapeutic target in distinct colorectal cancer subtypes.