NCI Scientists Launch Spotlight on Molecular Profiling
November 20, 2006
Field(s) of Research
: Cellular and Molecular Biology
Researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and their colleagues today introduced a new 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."
Cancer is a term that encompasses at least 200 different diseases characterized by genetic changes that alter the normal, controlled growth and division of cells. If cancer research in the pre-genomic era -- before the sequencing of the human genome -- was a cottage industry dedicated to the study of individual molecules and processes, then the post-genomic era is an industrial revolution. This new age is defined by technological advances, such as microarray platforms, that allow for the global, simultaneous study of the 20,000 to 25,000 genes that make up the human genome.
This new 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, the most extensively-profiled set of cells in existence. 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 more than 100,000 compounds for anti-cancer activity since 1990.
To examine this relationship, the researchers used microarray analysis, a powerful technology that measures activation levels for thousands of genes at once. 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, a recently developed genetic technique, 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."
The Cancer Genome Atlas (TCGA) is a three-year, 100 million dollar collaborative pilot project launched in December 2005 by NCI and the National Human Genome Research Institute, also part of the NIH. TCGA aims to use tissue samples derived from cancer patients to systematically explore the universe of genomic changes involved in several types of human cancers. Cell lines, including the NCI-60, are different from the clinical tumors that will be the focus of TCGA. Cell lines are unlimited in number, easy to manipulate, and valuable for repeating experiments under the same conditions, but they do not necessarily reflect all of the properties of tumors found in patients.
"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. Not all genetic changes are the same, not all cancers are the same, and they should not be treated as such," said Weinstein.
* 1) Weinstein JN, et al. Spotlight on molecular profiling: ''Integromic'' analysis of the NCI-60 cancer cell lines. Molecular Cancer Therapeutics 2006; Online November 7, 2006.
2) Lorenzi PL, Reinhold WC, Rudelius M, Gunsior M, Shankavaram U, Bussey KJ, Scherf U, Eichler GS, Martin SE, Chin K, Gray JW, Kohn EC, Horak ID, Von Hoff DD, Raffeld M, Goldsmith PK, Caplen NJ, Weinstein JN. Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells. Molecular Cancer Therapeutics 2006; Online November 7, 2006.
3) Ikediobi ON, Davies H, Bignell G, Edkins S, Stevens C, O'Meara S, Santarius T, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Hunter C, Jenkinson A, Jones D, Kosmidou V, Lugg R, Menzies A, Mironenko T, Parker A, Perry J, Raine K, Richardson D, Shepherd R, Small A, Smith R, Solomon H, Stephens P, Teague J, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Reinhold W, Weinstein JN, Stratton MR, Futreal PA, Wooster R. DNA sequence analysis of 32 known cancer genes in the NCI-60 cell lines Molecular Cancer Therapeutics 2006; Online November 7, 2006.
For more information on Dr. Weinstein's research and for a set of computer resources that include the databases and tools for integrating the data, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5816
For more information on NCI's genomic approach to cancer research, go to Integromic Analysis of the NCI-60 Cancer Cell Lines The Cancer Genome Atlas
NCI's Division of Cancer Treatment and Diagnosis provides resources to interested researchers at http://dtp.nci.nih.gov
For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).