Science & Technology - Posted by Kathy Svitil-Caltech on Wednesday, September 8, 2010 13:46 - 7 Comments 
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(4 votes, average: 5.00 out of 5) Loading ...RNA therapy turns cancer cells suicidal
In lab-grown human brain, prostate, and bone cancer cells, small conditional RNAs (light and dark blue) bind to a targeted RNA cancer mutation (orange and green), triggering self-assembly of a long double-stranded RNA polymer that activates an innate immune response (gray turns to red) leading to cell death. No measurable reduction in numbers is observed for cells lacking targeted cancer mutations. (Credit: Suvir Venkataraman, William Clemons Jr., and Niles Pierce/Caltech)
CALTECH (US)—Researchers have engineered a fundamentally new approach to killing cancer cells.
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The text of this article by Futurity is licensed under a Creative Commons Attribution-No Derivatives License.
The process uses small RNA molecules that can be programmed to attack only specific cancer cells; then, by changing shape, those molecules cause the cancer cells to self-destruct.
In conventional chemotherapy treatments for cancer, patients are given drugs that target cell behaviors typical of—but not exclusive to—cancer cells.
For example, cancer drugs commonly attack cells that divide rapidly, because such accelerated division is a hallmark of most cancer cells. Unfortunately, rapid cell division is a property of normal cells in the bone marrow, digestive tract, and hair follicles, and so these cells are also killed, leading to a host of debilitating side effects.
A better method, says Niles Pierce, associate professor of applied and computational mathematics and bioengineering at the California Institute of Technology (Caltech), is to create drugs that can first distinguish cancer cells from healthy cells and then, once those cells have been spotted, mark them for destruction—in other words, to produce molecules that diagnose cancer cells before eradicating them.
This type of therapy could do away with the side effects associated with conventional chemotherapy treatments. It also could be tailored on a molecular level to individual cancers, making it uniquely specific.
In a paper published online this week in the Proceedings of the National Academy of Sciences, Pierce and colleagues describe just such a process.
It employs hairpin-shaped molecules known as small conditional RNAs, which are less than 30 base pairs in length. (An average gene is thousands of base pairs long.)
The researchers’ method involves the use of two different varieties of small conditional RNA. One is designed to be complementary to, and thus to bind to, an RNA sequence unique to a particular cancer cell—say, the cells of a glioblastoma, an aggressive brain tumor.
In order to bind to that cancer mutation, the RNA hairpin must open—changing the molecule from one form into another—which, in turn, exposes a sequence that can spontaneously bind to the second type of RNA hairpin. The opening of the second hairpin then reveals a sequence that binds to the first type of hairpin, and so on.
In this way, detection of the RNA cancer marker triggers the self-assembly of a long double-stranded RNA polymer. As part of an innate antiviral immune response, human cells defend against infection using a protein called protein kinase R (PKR) to search for long double-stranded viral RNA, which should not be present in healthy human cells. If PKR indeed detects long double-stranded RNA within a cell, the protein triggers a cell-death pathway to eliminate the cell.
“The small conditional RNAs trick cancer cells into self-destructing by selectively forming long double-stranded RNA polymers that mimic viral RNA,” says Pierce. “There is, however, no virus.”
Researchers tested the process on lab-grown human cells derived from three types of cancers: glioblastoma, prostate carcinoma, and Ewing’s sarcoma (a type of bone tumor).
“We used three different pairs of small conditional RNAs,” with each pair designed to recognize a marker found in one of the three types of cancer, he explains. “The molecules caused a 20- to 100-fold drop in the numbers of cancer cells containing the targeted RNA cancer markers, but no measurable reduction in cells lacking the markers.”
For example, he explains, “drug 1 killed cancer 1 but not cancers 2 and 3, while drug 2 killed cancer 2 but not cancers 1 and 3, and drug 3 killed cancer 3 but not cancers 1 and 2.”
“Conceptually,” Pierce says, “small conditional RNAs provide a versatile framework for diagnosing and treating disease one cell at a time within the human body. However,” he notes, “many years of work remain to establish whether the conceptual promise of small conditional RNAs can be realized in human patients.”
The work was funded by the National Cancer Institute, the Elsa U. Pardee Foundation, the National Science Foundation’s Molecular Programming Project, and Caltech.
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7 Comments
Frances Morey
Candace Bonello
I have ovarian cancer. Two years ago I had two tumours removed – one from each ovary. I have been in remission until recently when my tumour marker CA125 increased from 30 to 110. I have tried using Artemisisin and Ganaderma as alternative treatments with as yet poor results. My tumour marker is now on 225.
I would be more than willing to get involved in any clinical trials pertaining to your RNA research.
I look forward to hearing from you.
Best Regards
Candace
Niles Pierce
Dear Candace,
We are working as hard as we can to push ahead with the next phases of the research. If further studies are successful (which is always a big “if” with research), we would hope to begin clinical trials within a few years, but I’m afraid we’re not at that point yet. I wish I had better news.
Niles Pierce
Greg
Frances: Big Pharma makes billions from “treating” cancer, not curing it. It is in their best interest not to find a cure.
Frances Morey
I had hoped the money for the basic research could come in an outpouring from government sources as it did for AIDS. Finding a cure would “save” Medicare and Medicaid billions. But then again bringing the costly and unwarranted wars to an end would free up monies for better uses as well.
Dear Dr. Pierce, This is astonishing! I had no idea such work was being done and that you are so well on your way. I recently read Crichton’s book, PREY, involving nanotechnology, a cautionary tale to be sure but, nonetheless, an introduction to the world you are opening up. How excited you and your team must be. One small step for a man, a giant leap for mankind.
Ben, RN
Dear Dr. Pierce, Targeted therapy would be an excellent way to treat and possibly cure cancer, especially those that don’t respond to current methods of treatment. The challenge is in the details. Making that transition from the lab to treatment is never easy. Hopefully, we can help those patients with bridge therapy until your research produce definite regimens leading to a cure. All things considered, our government’s priorities are not (to say the least) in-line. We need dedicated people: researchers, doctors, pharmacists, engineers, nurses, lab technicians to carry out the job. That is the mission.
When they come up with a breakthrough theory like this can’t they bombard it with enough money to shorten the time line to reach the stage for human testing and treatment? This sounds so promising.