Telomerase Inhibition in Tumor-Initiating Cells
Castelo-Branco et al., Page 111
Telomerase activation is a major mechanism governing tumor self-renewal and plays an important role in relapse of pediatric tumors. Here, Castelo-Branco and colleagues studied telomerase activation in glioma samples. They found that telomerase was absent in the majority of tumor cells and was only active in the tumor-initiating cell (TIC) cancer subpopulation. Telomerase inhibition resulted in TIC exhaustion due to irreversible loss of self-renewal capabilities. In contrast, normal neural stem cells had undetectable telomerase activity and were insensitive to telomerase inhibition. Targeting TIC self-renewal may represent a novel and safe therapeutic approach to prevent tumor recurrence in pediatric cancers.
Environmental Tobacco Smoke and EGFR Mutations
Kawaguchi et al., Page 39
Some studies have suggested that epidermal growth factor receptor (EGFR) mutations play a critical role in the carcinogenesis of lung cancer in never-smokers. To explore the involvement of environmental tobacco smoke in this process, Kawaguchi and colleagues administered a detailed questionnaire to never-smokers with non-small cell lung cancer. They found that female gender and longer exposure to environmental tobacco smoke were significantly associated with activating EGFR mutations. These findings suggest that long and low-dose carcinogen exposure may affect the development of EGFR mutations in never-smokers with lung cancer.
Tumor Targeting with a DARPin-Toxin Fusion Protein
Martin-Killias et al., Page 100
Designed ankyrin repeat proteins (DARPins) are useful binding molecules for tumor targeting that lack some limitations of antibodies. Here, Martin-Killias and colleagues used a high-affinity DARPin (specific for the carcinoma-associated antigen EpCAM) and a truncated form of Pseudomonas exotoxin A to generate a new fusion toxin. The fusion toxin expressed well in bacteria and specifically reduced the viability of EpCAM-positive carcinoma cells in vitro. Further, the fusion toxin showed potent antitumor effects in vivo, and optical imaging of tumor-xenografted mice showed efficient tumor localization. This DARPin-toxin fusion protein holds promise for clinical development to improve tumor targeting.
Clinical Relevance of Lung Cancer Xenograft Models
John et al., Page 134
Cell lines have been used extensively in cancer research to study aberrant pathways and evaluate therapeutics. Recently, interest has grown in primary tumor xenografts because they may represent more clinically relevant models. However, not all non-small cell lung cancer (NSCLC) tumors implanted into mice grow. To explore factors associated with engraftment, John and colleagues implanted 157 resected NSCLC tumors into immunosuppressed mice. They found that squamous cell, poorly differentiated, and KRAS mutant tumors had higher rates of engraftment. The ability to engraft was a strong independent predictor of early relapse for patients, suggesting engrafting tumors are biologically more aggressive.