Cancer cells are characterized by genetic mutations that deregulate cell proliferation and suppress cell death. To arrest the uncontrolled replication of malignant cells, conventional chemotherapies systemically disrupt cell division, causing diverse and often severe side effects as a result of collateral damage to normal cells. Seeking to address this shortcoming, we pursue therapeutic regulation that is conditional, activating selectively in cancer cells.
This was an interesting paper that caught my eye in PNAS last night. Further reading demonstrated that the process uses small RNA molecules. The idea behind this approach was that the small RNA molecules can be programmed to attack only specific cancer cells; then, by changing shape, those molecules cause the cancer cells to self-destruct.
Normal cells die after a period of time and are replaced by new ones, a process called programmed cell death or apoptosis. In a tumour, the cells continue to proliferate and form a mass, growing new blood vessels to feed the structure via angiogenesis.
One of the things that has absorbed researchers for years is how to stop that process and induce cell death in cancer cells without killing a lot of normal cells at the same time. To do this, we need to find ways of distinguishing cancerous from normal cells, thereby inducing a more targeted and selective approach to destruction and reducing unwanted side effects. ]
This is not as easy as it sounds though!
In the PNAS study, the researchers took small conditional RNAs, which are less than 30 base pairs in length and are hairpin shaped molecules as shown in the photo below.
The press release from Caltech described the concept as thus:
"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."
Essentially, this is a clever way to use small conditional RNAs to the trick cancer cells into self-destructing by selectively forming long double-stranded RNA polymers that mimic viral RNA.
The researchers tested the RNA concept in the lab in xenograft models derived from three types of cancers: glioblastoma, prostate carcinoma, and Ewing's sarcoma so far, with some success:
"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."
Now clearly this approach has a long way to go before we see it in clinical trials, but there's nothing like starting off your day with exciting new technology approaches that may have application in the near future.
We need more creative research like this in oncology!
Photo Credit: Caltech
Venkataraman, S., Dirks, R., Ueda, C., & Pierce, N. (2010). Selective cell death mediated by small conditional RNAs Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1006377107