Highlights of This Issue Free

Squamous cell carcinomas (SCC) with infiltrative invasion carry a higher risk of treatment failure. Here. Basu and colleagues showed SCCs with infiltrative, high-risk invasion patterns contain frequent mesenchymal-like tumor cells. Such tumors were modeled using collagen-embedded spheroids, which revealed distinct fronts created by collective migration of E-cadherin–positive cells versus infiltration of mesenchymal-like cells. Anti-EGFR treatment of spheroids enhanced infiltration by selectively sparing the mesenchymal-like cells, and similar findings were observed in xenografts. These results implicate mesenchymal-like SCC cells as mediators of the infiltrative invasion and demonstrate that anti-EGFR drugs may promote such invasion if this cellular phenotype is present.

The serine protease granzyme B (GrB) induces apoptosis through both caspase-dependent and caspase-independent multiple-cascade mechanisms. Vascular endothelial growth factor 121 (VEGF₁₂₁) binds to both VEGFR-1 and VEGFR-2 receptors. Mohamedali and colleagues engineered a unique GrB/VEGF₁₂₁ fusion protein that localized efficiently into VEGFR-2–expressing cells in vitro. Administration of GrB/VEGF₁₂₁ on mice bearing established PC-3 tumor xenografts showed significant antitumor effect in vivo. GrB/VEGF₁₂₁ facilitates the targeted delivery of granzyme B to tumor vascular endothelial cells or to tumor cells and activates apoptotic cascades. This completely human construct may have significant therapeutic potential.

Improving patient outcome involves thorough understanding of an agent's mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme NAD(P)H:quinone oxidoreductase (NQO1). In this study, utilizing NQO1-positive human breast cancer cells, Bey and colleagues discovered that β-lapachone–induced lethality could be abrogated by exogenous catalase addition. Exposure to exogenous catalase or genetic overexpression of catalase abrogated β-lapachone–induced lethal events including ROS formation, PARP-1 hyper-activation, γH2AX foci formation, and the release of AIF from mitochondria. These studies suggest that evaluation of NQO1/catalase ratios may improve patient outcomes.

The emergence of resistance to EGFR inhibitor therapy is a major clinical problem for treatment of non–small cell lung cancer (NSCLC) patients. In this report, Li and his colleagues have demonstrated that erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway contributes to acquired resistance to erlotinib. Disruption of STAT3 by niclosamide reverses erlotinib resistance and synergizes with erlotinib against lung cancer in vitro and in vivo. Based on their findings, the combined treatment of niclosamide and erlotinib could represent a novel and more effective therapeutic strategy for improving the outcome of NSCLC patients, including those who have already developed resistance to standard EGFR-TKI therapy.