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NCI Scientists Launch Spotlight on Molecular Profiling

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Researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and their colleagues have introduced a series of research articles, "Spotlight on Molecular Profiling," in the November 7, 2006, issue of "Molecular Cancer Therapeutics". 

The series will highlight molecular profiling studies that provide broad-spectrum genomic and proteomic data that could prove useful for the discovery of new drugs and biomarkers.

The first article published in the series shows how such profiles can be used to discover a new biomarker that might someday help to personalize treatment of ovarian cancer. This study, as well as a commentary on molecular profiling, opens the series.

"Rather than forming a hypothesis about a specific gene or protein and designing experiments to test it, molecular profiling takes a more global approach to cancer research," said NCI Director John Niederhuber, M.D.

"This technique surveys the expression of thousands of genes in a single experiment to map the changes in the human genetic blueprint associated with cancer."

"The molecular profiling approach will accelerate our understanding of the molecular basis of cancer and will lead to new insights for the treatment, detection, and prevention of these diseases." 

This series of articles will examine and compare genetic profiles of different cancer types toward the goal of developing tools to personalize anticancer strategies.

"The real value of molecular profiling will be realized when biomedical scientists with a particular expertise are able to integrate and use the data fluently for hypothesis generation, hypothesis-testing, and what I would term 'hypothesis-enrichment'," said John Weinstein, M.D., Ph.D., head of the Genomics and Bioinformatics Group at NCI.

In one of the inaugural articles in the Spotlight series, Weinstein and his colleagues used a panel of 60 human cancer cell lines, known as the NCI-60 panel, to analyze the actions of L-asparaginase (L-ASP), a bacterial enzyme that has been used since the 1970s to treat acute lymphoblastic leukemia.

L-ASP scavenges the blood, chewing up molecules of free asparagine, one of 20 amino acids needed to build proteins in a cell.

Normal cells can use the enzyme asparagine synthetase (ASNS) to make their own asparagine, but L-ASP selectively starves cancer cells that cannot produce enough of the amino acid for their own needs.

Since recent studies have suggested a link between L-ASP activity and ASNS, the NCI research team analyzed activation of the ASNS gene in the NCI-60 cancer cell lines.

Each cell line originated from a single cell type taken from a cancer patient and was then transformed in the lab to grow indefinitely outside the body.

The NCI-60 panel of cells has been used by NCI's Developmental Therapeutics Program to screen 100,000 compounds for anti-cancer activity since 1990. To examine this relationship, the researchers used microarray analysis.

In this study, five different microarray platforms used in the molecular profiling of the NCI-60 revealed a strong correlation between the anticancer activity of L-ASP and reduced activation of the ASNS gene in ovarian cell lines.

Subsequently, the researchers and their collaborators used RNA interference to reduce the activation level of ASNS five-fold in one of those cell lines.

As a result, L-ASP became over 500 times more effective at killing the cancer cells, suggesting that ASNS levels are the principal determinant of L-ASP activity.

Furthermore, this increased activity was maintained in ovarian cancer cells that had developed classical multi-drug resistance to other forms of treatment.

"We are hopeful that the level of ASNS expression may one day be useful as a tool for selecting ovarian cancer patients who will most benefit from the use of L-ASP," said Philip Lorenzi, Ph.D., NCI, lead author of the study.

"This study provides an example of what the NCI-60 cell line panel can do that is complementary to a different NCI-sponsored study, The Cancer Genome Atlas, which is profiling clinical tumors."

"This emphasis on molecular profiling reflects a shift in research from small-scale to large-scale efforts, which are necessary because the genetic changes that lead to cancer occur in the context of whole genomes," said Weinstein.

"Not all genetic changes are the same, not all cancers are the same, and they should not be treated as such."