Some small RNA molecules can selectively kill cultured human cancer cells, leaving healthy cells untouched, according to a study published online yesterday (6th September) in PNAS -- a feat that has surpassed conventional cancer therapies that kill indiscriminately, causing an array of side effects in patients.

Prostate cancer, a possible target for this therapy. Image: Wikimedia commons, user Nephron

"It's a novel approach that will bring about new and cool things in the field," said Andrew Ellington, a biotechnologist at the University of Texas at Austin, who was not involved in the research. And with 7.6 million cancer-related deaths worldwide in 2007, according to the American Cancer Society, there is an "urgent need for new approaches to cancer treatment," Niles Pierce, bioengineer at the California Institute of Technology and lead author of the study, said in an email to The Scientist.

While traditional chemotherapies effectively annihilate cancer cells, they take out many healthy cells in the process, often causing hair loss, nausea, anemia, and other unpleasant side effects. Specifically targeting cancer cells has proven elusive in the search for new and better cancer therapies because treatment has centered upon stunting rapid cell division, which is not unique to cancer cells. Conversely, a relatively new approach called RNA interference (RNAi) concentrates on distinguishing the oncogene, but fails to effectively kill the cancer.

In search of a selective and effective cancer killer, Pierce and his colleagues decided to use the oncogene's characteristically high quantity of deletions and insertions, and other mutations against it. They engineered small RNA molecules known as small conditional RNAs that, like other small RNAs, use these unique mutations to distinguish specific sequences of bone, brain, and prostate cancer from the RNA of a normal cell. But in addition to recognizing cancer cells, small conditional RNAs also kill them.

The binding of the small conditional RNAs to the mRNA cancer marker triggers a chain reaction that produces a virus-resembling RNA polymer. This polymer then prompts an innate anti-viral immune response, which causes the cancerous cell to undergo apoptosis.

In all three types of cancer tested, the researchers saw a 20- to 100-fold reduction in the number of cells containing the targeted cancer mutations after they injected the small conditional RNAs, but no noticeable decrease in normal cells, demonstrating the method's selectivity and efficacy.

"Conceptually, small conditional RNAs have the potential to transform cancer treatment because they change what we can expect from a therapeutic molecule," said Pierce. "However, many years of work remain to establish whether this conceptual promise can be realized in human patients."

"At the moments it's a great idea, but it has to be tested on animals," agreed Alexander Levitzki, biochemist at the Hebrew University of Jerusalem, who did not participate in the study.

Still, this is a step in the right direction for the development of an effective targeted cancer therapy. It adds to research led by John Rossi at Beckman Research Institute of City of Hope, who started conducting human trials of therapeutic RNA interference (RNAi). While with RNAi therapy, which employs small RNA molecules known as non-conditional small RNAs, can be designed to target diverse disease-related mRNA sequences, the therapy is not as effective at killing those diseased cells. The new technique combines the selectivity of RNAi with the added ability to initiate a chain reaction that leads to the cell's death.

A major challenge that still faces any technique using small RNAs to treat cancer is the ability "to deliver the molecules into cancer cells within the human body," said Pierce Fortunately, he added, many groups are working on this problem for the small RNAs used in RNAi therapies, and their findings "will significantly benefit future translational efforts with small conditional RNAs," as well.

"Small conditional RNAs may still be a radical concept," said Pierce, "but we think they have a chance of providing a powerful framework for treating cancer as well as some other diseases."

S. Venkataraman et al., "Selective cell death mediated by small conditional RNAs," PNAS, doi: 10.1073/pnas.1006377107

Editor's Note (7th December 2010): When originally posted, the article stated that Alexander Levitzki was a retired biochemist. He is actually not retired. The Scientist regrets the error.


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