Highlights of This Issue

The median survival for glioblastoma is less than 2 years. Using human glioblastoma stem-like cell (GSC) lines isolated via a marker-neutral strategy, Zorniak and colleagues tested the hypothesis that GSC lines express distinct neural developmental protein profiles with clinical utility. They found that differential neural lineage protein expression was correlated with extent of tumor infiltration and survival in mouse xenografts. Expression of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), a marker of oligodendroglial progenitors, was correlated with patient survival in a large clinically annotated glioblastoma tissue microarray. These data link developmental neural markers with tumor infiltration and patient survival and reveal CNP as a novel marker for glioblastoma prognosis.

Medullary thyroid carcinoma (MTC) responds poorly to conventional chemotherapy or radiotherapy. An understanding of the molecular pathways driving MTC formation would be helpful in the design of targeted therapeutics for patients with advanced disease. Tamburrino and colleagues show that the mTOR pathway is consistently activated in MTC, that such activation is robust in MTC metastases, and that the expression of neoplastic phenotype depends on mTOR activity. Targeting mTOR with rapamycin or its derivatives may be exploited as a therapeutic strategy for metastatic MTC.

Although crizotinib shows dramatic effects against EML4-ALK lung cancer cells, these cells can acquire resistance, which selective ALK inhibitors may be able to overcome. Yamada and colleagues show that epidermal growth factor receptor ligands and hepatocyte growth factor produced by cell microenvironments can cause EML4-ALK lung cancer cells to become resistant to crizotinib and/or selective ALK inhibitors by triggering bypass survival signals. These findings raise clinical questions about the class of ALK inhibitors that would be more beneficial for patients with EML4-ALK lung cancer. Moreover, these results provide a rationale for targeting receptor ligands in the microenvironment for more successful treatment of these patients with ALK inhibitors.

The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In a phase I clinical study conducted by Sawada and colleagues, 33 patients with advanced HCC underwent GPC3 peptide vaccination. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. These results show that GPC3 peptide-specific CTLs appeared in peripheral blood and that many CD8-positive T cells infiltrated tumors after vaccination. GPC3 peptide-specific CTL frequency was correlated with overall survival in HCC patients receiving peptide vaccination. These observations suggest that GPC3-derived peptide vaccines could be a novel therapy for HCC patients.