December 15 Clinical Cancer Research Highlights

PDF Version for Printing

Selected Articles from the December 15, 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 Clinical Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the December 15 issue of Clinical Cancer Research.

Targeting the Cell Death-Survival Equation

This CCR Focus comprises five articles that deal with substantively different aspects of the process by which cell death is governed in nature. Benz and coauthors begin with an overview of targeting the cell death-survival equation. Danial follows with a review of the structure and function of the BCL-2 family of proteins and their potential role in disorders as apparently disparate as cancer and diabetes. In the third article, Verdine and Walensky return to apoptosis and show that the alpha helices of BH3 death domains can be made into drugs by means of peptide stapling and actually induce apoptosis in cancer cells. In the next article, Amaravadi and Thompson broadens the discussion of cell death to include a penetrating analysis of the roles of necrosis and autophagy in cancer treatment. Finally, Rixe and Fojo emphasize that effective cancer treatment can occur by inducing cytostasis rather than cytotoxicity because cytostasis is often poorly tolerated in tumor cells and, if sustained, should lead to cell death.

BRCA1 mRNA Predicts Survival in Ovarian Cancer

RPPA Measures Pharmacodynamic Effects of Targeted Therapies

Recent studies suggest that perifosine inhibits the phosphatidylinositol-3’-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin-homology (PH) domain.  Hennessy and colleagues sought to establish the utility of a novel functional proteomics technology, reverse phase protein microarrays (RPPA), for measuring pharmacodynamic effects of targeted therapies. They showed in cell line and xenograft models that PI3K pathway biomarkers are likely to be the most useful early pharmacodynamic markers of biologically relevant dosing of perifosine. This is based on a strong correlation between proportional modulation of these biomarkers as measured by RPPA and quantified perifosine efficacy. It is likely that adopting this approach to study other targeted therapies will maximize our ability to select responding patients early on and guide optimal dosing. 

Because the generation of reactive oxygen species by activation of membrane nonmitochondrial NADPH oxidase appears to be one mechanism regulating cell growth contributing to pancreatic tumor progression, Teoh and colleagues hypothesized that scavenging of superoxide generated from the plasma membrane would also inhibit pancreatic cancer growth. The investigators showed that scavenging of superoxide with the antioxidant enzymes extracellular superoxide dismutase and copper zinc superoxide dismutase has a stronger tumor suppressive effect in pancreatic cancer. Thus, scavenging plasma membrane–generated superoxide may prove beneficial for suppression of pancreatic cancer growth.