Highlights of This Issue

Accurate classification of cancers improves our understanding of their biologic diversity. However, past studies have often relied on one data type. Li and colleagues performed combined analyses of DNA, mRNA, and promoter methylation data for the same series of glioblastoma multiforme samples and proposed a new classification system in which approximately 50% of the previously defined proneural samples were reassigned. The new system has improved correlations to patient outcome and provided clearer correspondence to known cell types. These results clarify a long-standing confusion regarding the proneural group and identify the microglia/macrophage as the potential euploid source for the mesenchymal subtype.

By comparing and integrating genomic copy-number and mRNA tumor profiles from never smokers and ever smokers, Fouret and colleagues revealed evidence indicating that the amplified ATPase family, AAA domain containing 2 (ATAD2), is the driving force behind MYC contribution to uncontrolled cell proliferation in lung adenocarcinoma. This finding may have clinical consequences because ATAD2 inhibition may circumvent the difficulty of specifically inhibiting MYC in lung cancers.

Successful application of the proteasome inhibitor bortezomib for the treatment of solid tumor malignancies has been hindered by poor efficacies and cytotoxicities and a lack of oral bioavailability. Zang and colleagues show that the second-in-class proteasome inhibitors carfilzomib and ONX 0912 are potently active against head and neck squamous cell carcinoma (HNSCC). Notably, oral administration of ONX 0912 resulted in marked inhibition of HNSCC tumor growth in vivo. Carfilzomib and ONX 0912 activities were enhanced following inhibition of autophagy or suppression of Mcl-1 expression. These findings suggest that carfilzomib and ONX 0912 may provide therapeutic benefit in HNSCC.

Due to resistance mechanisms, treatment with imatinib for gastrointestinal stromal tumors (GIST) will ultimately lead to progressive disease. To explore the role of pharmacokinetic resistance, Eechoute and colleagues followed GIST patients treated with this drug prospectively for at least 1 year to determine long-term imatinib systemic exposure. They found that the plasma area under the curve for this drug dropped to approximately 30% within 3 months of treatment, which may have serious consequences for antitumor activity. The role of liver metastases in the clearance of imatinib is very limited.