Molecular Profiling Informs Ovarian Cancer Therapy
NCI researchers are reporting that ovarian cancer cells with diminished ability to produce asparagine may be susceptible to the drug L-asparaginase (L-ASP), which has been used for more than 30 years to treat acute lymphoblastic leukemia. L-ASP metabolizes asparagine in the blood, selectively starving some types of 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 asparagine synthetase (ASNS) expression, the research team, led by Dr. John Weinstein, head of the Genomics & Bioinformatics Group (GBG) in NCI's Center for Cancer Research (CCR), analyzed expression of the ASNS gene in the NCI-60 panel of human cancer cell lines. The NCI-60 panel, used by NCI's Developmental Therapeutics Program to screen more than 100,000 compounds and natural products since 1990, is the most extensively profiled set of cancer cells in existence. Five different microarray platforms that GBG and their collaborators used for molecular profiling of the NCI-60 panel revealed a strong relationship between the anticancer activity of L-ASP and low expression of ASNS in ovarian cancer cell lines.
When the researchers and their collaborators then used RNA interference to reduce the expression of ASNS fivefold in three of those cell lines, L-ASP became much more active. With the cell type that expressed the least ASNS, the activity of L-ASP increased more than 500-fold, and that enhanced killing was maintained in a classically multidrug resistance cell line.
"We hope the level of ASNS gene activation will one day be a useful tool for identifying ovarian cancer patients who will benefit from L-ASP treatment," said lead author Dr. Philip Lorenzi, a Pharmacology Research Associate Program fellow in GBG. "However, it should be remembered that results in cell lines don't necessarily reflect what will happen in clinical tumors."
The group's collaborators have opened a phase I clinical trial to test the safety of L-ASP in patients with solid tumors and non-Hodgkin's lymphoma and to begin assessment of ASNS as a biomarker.
The ASNS study, published online November 7 in Molecular Cancer Therapeutics, launches a new "Spotlight on Molecular Profiling" series of articles, which will highlight high-quality molecular profiling research and provide genomic and proteomic data for many types of cancer.
According to their interests and expertise, researchers around the world will be able to mine the molecular profiles published in the series with the ultimate goal of developing personal molecular profiles and improving cancer detection, treatment, and prevention. To facilitate those uses of the data, GBG has developed an interactive database and set of query tools called "CellMiner."
"If cancer research in the pregenomic era was a cottage industry dedicated to the study of individual molecules and processes, then the postgenomic era is an industrial revolution defined by technological advances that allow for large-scale screening of thousands of genes at once," Dr. Weinstein concluded. "This new spotlight on molecular profiling is important because it will emphasize that not all genetic changes are the same and not all cancers are the same, and they should not be treated as such."
By Heather Maisey