American Association for Cancer Research

August 2007 Molecular Cancer Therapeutics Highlights

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Selected Articles from the August 1, 2007 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Molecular Cancer Therapeutics is published. Click on the article title to view the complete article.

View the Table of Contents for the August 2007 issue of Molecular Cancer Therapeutics

IGF-II-dependent Colon Cancer Blocked

Ji et al.

Page 2158

The insulin-like growth factor-I receptor (IGF-1R) is especially critical for human colorectal cancer which may drive its own growth and survival through autocrine IGF-II expression. PQIP is a novel and orally potent small molecule IGF-1R kinase inhibitor with 14-fold cellular selectivity over the human insulin receptor. Ji and coauthors found that PQIP showed robust anti-tumor efficacy in GEO xenografts, which correlated with inhibition of tumor IGF-1R phosphorylation in mice. When treated with PQIP, mice showed only minor changes in blood glucose. Thus, PQIP represents a potent and selective class of IGF-1R kinase inhibitors that may be especially efficacious in treatment of IGF-II-dependent human cancers.
 

Erlotinib Resistance Explored

Yamasaki et al.

Page 2168

Inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinases such as erlotinib and gefitinib have not been very effective in the treatment of breast cancer even though many breast cancer cells express EGFR. To address this apparent paradox, Yamasaki and colleagues examined possible predictors of the sensitivity of 10 breast cancer cell lines to erlotinib in light of cyclin-dependent kinase 2 (CDK2), considered the farthest downstream kinase that controls cell cycling in the EGFR signaling pathway. Their findings indicated that the ability of erlotinib to suppress of CDK2 activity is critical for cellular sensitivity to erlotinib, regardless of EGFR expression level, and that the presence of p27 in the cytoplasm also participates in erlotinib resistance.

Radioresistant Nasopharyngeal Cancer Profiled

Chang et al.

Page 2271

Radiotherapy is the major treatment modality for nasopharyngeal cancer, but in some cases the disease is radioresistant (RR). To profile RR associated transcriptome, Chang and colleagues established two NPC-RR subclones which were then subjected to cDNA microarray analysis and compared to their parental cell lines. Seven genes were found over-expressed in the RR subclones, including gp96 and GDF15. Knockdown gp96 or GDF15 by siRNA significantly caused radiation-induced growth delay, reduced colonogenic survival, and increased the proportion of the cells in G2/M phase, the most radiosensitive phase of the cell cycle. These results suggested that the roles of these genes in radioresistance and demonstrate that knockdown of the genes enhances radiosensitivity in NPC.

Low-dose metronomic, antiangiogenic chemotherapy (e.g. using cyclophosphamide) has shown promise in phase II trials. Although less toxic, it may present new issues compared to conventional, maximum-tolerated dose chemotherapy such as possible altered biotransformation and endothelial cell tachyphylaxie due to long-term drug administration, potentially resulting in acquired resistance. A pharmacological and pharmacodynamic analysis by Emmenegger and colleagues of oral low-dose metronomic cyclophosphamide given to mice did not reveal any indication for altered cyclophosphamide biotranformation or tachyphylaxie after long-term daily oral therapy. These findings suggested that acquired resistance might instead be related to adaptive processes in the tumor cell population as opposed to the tumor vasculature.

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