Weakened RNA Interference Reduces Survival In Ovarian Cancer
Main Category: Cancer / OncologyAlso Included In: Women's Health / Gynecology; Genetics
Article Date: 18 Dec 2008 - 4:00 PDT
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Levels of two proteins in a woman's ovarian cancer are strongly associated with her likelihood of survival, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Dec. 18 issue of the New England Journal of Medicine.
The study shows that women with high levels of Dicer and Drosha, two proteins that are vital to a cell's gene-silencing machinery, had a median survival of 11 years. For those with low levels of either or both proteins, median survival was 2.66 years.
"Dicer and Drosha are crucial for two types of RNA interference, which cells use to shut down genes. We've found that when this machinery is disrupted, patient outcomes are poor," said senior author Anil Sood, M.D., professor in the departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson. The study is the largest and most comprehensive demonstration of the connection between RNA interference and cancer.
The researchers also analyzed gene expression data in groups of lung and breast cancer patients and found similar associations with patient survival.
"Very consistently, we found that low levels of Dicer in particular are predictive of poor outcomes," Sood said. Molecular details of the raised risk for patients remain to be discovered, but it is likely that low levels of Dicer and Drosha permit some genes to continue functioning when they should be silenced.
"RNA interference has only been known for about a decade. The components of the machinery, what it does in cancer, and how it affects outcomes and therapy are not fully known," Sood said.
Potential clinical applications include using levels of the proteins as prognostic indicators to guide treatment decisions and eventually to exploit RNA interference to attack tumors, Sood said.
Interfering with gene expression
The team measured expression levels of Dicer and Drosha in 111 invasive ovarian cancer tumors and then compared the results to the patients' clinical outcomes. The initial findings were supported by a second analysis of gene expression in a different group of 132 ovarian cancer patients.
Analysis of 91 patients with lung cancer and 129 breast cancer patients reached similar conclusions, however, only Dicer levels were found to affect survival.
Drosha and Dicer are involved in the production of short interfering RNA (siRNA) and micro interfering RNA (miRNA). Genes express messenger RNA to tell a cell's protein-making machinery what protein to make. SiRNA and miRNA work by either cleaving the target messenger RNA or preventing protein production. Both types of interfering RNA are tiny, with the main difference that miRNA consists of a single strand of RNA while siRNA starts out double-stranded.
Statistical analysis of five risk factors for ovarian cancer showed that only low Dicer levels, high-grade tumors and poor response to chemotherapy are independent predictors of survival. "When we find a new prognostic factor for cancer, we conduct a multivariate analysis to make sure that it's not associated with known factors, such as tumor grade. In this case, low Dicer levels were completely separate from traditional predictive factors," Sood said.
A genetic analysis of the Dicer and Drosha genes turned up mutations in both, but none that were associated with high or low levels of the proteins.
siRNA's potential for treatment
Sood and colleague Gabriel Lopez-Berestein, M.D., professor in M. D. Anderson's Department of Experimental Therapeutics, are developing cancer drugs that deliver a siRNA via fatty nanoparticles to silence a specific cancer-causing gene.
"We've found that another type of RNA, short hairpin RNA (shRNA) silences genes in a stable manner rather than the transient effects attributed to siRNA," said study senior co-author Menashe Bar-Eli, Ph.D., professor of Cancer Biology. However, animal models showed that these longer shRNA fragments could not silence genes in some cells. The authors found that about half of ovarian cancer cells either had low levels of Dicer and Drosha or lacked one or both proteins altogether.
A functional test of Dicer and Drosha for the project showed that shRNA does not work well with low levels of Dicer. When Dicer is low, siRNA still works. "This suggests that for therapeutic purposes, siRNA might be the better option as we develop new treatments based on interfering RNA," said co-author Robert Coleman, M.D., professor of gynecologic oncology.
The research was supported by grants from the National Cancer Institute, including the Specialized Program in Research Excellence to study ovarian cancer, the Ovarian Cancer Research Fund Program Project Grant, the Gynecologic Cancer Foundation, the Zarrow Foundation, the Betty Anne Asche Murray Distinguished Professorship, the Marcus Foundation, and the U.S. Department of Energy Office of Science, Office of Biological and Environmental Research.
Co-authors with Sood, Lopez-Berestein, Coleman and Bar-Eli are first author William Merritt, M.D., Yvonne Lin, M.D., Liz Han, M.D., Aparna Kamat, M.D., Whitney Spannuth, M.D., Rosemarie Schmandt, M.D, and Alpa Nick, M.D., all of M. D. Anderson's Department of Gynecologic Oncology; Diana Urbauer, and Peter Mueller, Ph.D., of M. D. Anderson's Department of Biostatistics; Michael Deavers, M.D., of M. D. Anderson's Department of Pathology; and Alexandra Mourad-Zeidan, Ph.D., of the Department of Cancer Biology; Len Pennachio, Ph.D., Jan-Fang Cheng, Ph.D., and Joe Gray, Ph.D., of Lawrence Berkeley National Laboratory; Marc Lenburg, Ph.D., and Hua Wang, Ph.D., of Boston University School of Medicine; Samuel Mok, Ph.D., of Brigham and Women's Hospital in Boston; and Michael Birrer, M.D., Ph.D., Center for Cancer Research, Bethesda, MD.
About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For four of the past six years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.
University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd., Box 229
Houston
TX 77030
United States
http://www.mdanderson.org
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Genetic Differences To Determine Clinical Responders
posted by Gregory D. Pawelski on 19 Dec 2008 at 9:13 amMicroarrays (gene chips) examine what genes are expressed in cancer cells. It is mainly used for screening/gene discovery work. You screen 50,000 genes to discover an association and then you focus in on only a few hundred or so for more careful study by some other method like real time polymerase chain reaction (RT-PCR).
Genes make proteins, the molecules that comprise and maintain all the body's tissues. Genes produce their effect by sending molecules called messenger RNA to the protein-making machinery of a cell. They set the protein-making machinery in motion through a "gofer" messenger called RNA (or mRNA).
The technique called RNA interference (RNA-i) allows scientists to "silence" certain genes. In RNA interference, certain molecules trigger the destruction of RNA from a particular gene, so that no protein is produced. Thus, the gene is effectively silenced. RNA interference is already being widely used in basic science as a method to study the function of genes and it is being studied as a treatment for cancer.
This RNA interference occurs naturally in plants, animals, and humans. RNA interference is important for regulating the activity of genes (a fundamental mechanism for controlling the flow of genetic information). RNA interference (RNAi) interferes with mRNA, a natural molecular switch, regulating gene expression in plants, animals and humans, by "silencing" over-active or malfunctioning genes.
The ability to introduce foreign DNA into cultured cells with DNA gene sequences has allowed us to assign functions to different genes and understand the mechanisms that activate or redress their function. It has made gene therapy research possible, like with the proteins Dicer and Drosha.
However, giving instructions on the genetic differences that determine how a person responds to a drug will still have cancer medicine being prescribed on a "trial-and-error" basis, with adverse drug reactions remaining a major cause of injury and hospitalizations.
All the gene mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. The don't tell you if one drug is better or worse than some other drug which may target this.
The cell is a system, an intergrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, before you find clinical responders.
Genetic profiles cannot discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can they identify situations in which it advantageous to combine a targeted drug with other types of conventional cancer drugs.
Two years ago, three federal agencies, NCI, FDA, and CMS, announced a program to try to identify biological indicators, or biomarkers, which may indicate whether a cancer patient is likely to benefit from a given anti-cancer therapy, or even whether they will suffer from certain side effects.
We have the biomarkers for who will respond so we don't give these powerful and expensive medicines to those who won't. Technologies, developed over the last twenty years by private researchers, hold the key to solving some of the problems confronting a healthcare system that is seeking ways to best allocate available resources while accomplishing the critical task of matching individual patients with the treatments most likely to benefit them.
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