Can Cancer Cells Be Tricked into Committing Suicide?

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Imagine: if malignant tumor cells can be tricked into killing themselves without affecting normal cells, then maybe a cure for cancer is here! This sounds too good to be true, but Dr. David Stojdl, a scientist from the Children’s Hospital of Eastern Ontario Research Institute has found a novel way to induce resistant cancer cells into committing suicide following oncolytic virus therapy.

The Use of Oncolytic Viruses for Cancer Therapy

Children's Hospital of Eastern Ontario: Photo by Craig Allsop

The study of using viruses to destroy cancer cells, or oncolytic virology, is becoming more popular with the development of advanced genetic-engineering techniques. Scientists have developed viruses that preferentially target cancer cells, both by direct destruction of the tumor cells and by acting as vectors enabling “suicide” genes to be delivered specifically to the tumor site. Until recently, the focus of researchers has been on engineering the genes in the oncolytic virus itself to make them work better at targeting cancer cells. Once they are able to invade these cells they replicate inside and destroy them. This proceeds like a chain reaction to adjacent malignant cells without affecting normal cells, which they don’t recognize.

RNA Interference (RNAi)

Recently, a team of scientists headed by Dr. David Stojdl of the Children’s Hospital of Eastern Ontario Research Institute at the University of Ottawa (Canada) found a more promising method of destroying malignant tumor cells in mice using a technology called RNA Interference (RNAi).  What is RNAi? It is a natural process that cells use to suppress the activity of specific genes.

The researchers probed systematically through the human genome, which consists of the entirety of man’s hereditary information contained in the genes, to find those that may be inhibited.

The role of RNAi in cancer therapy is being studied to suppress over-active gene activity in these cells. Once the activity of cancer cells is weakened or suppressed, oncolytic viruses can become more potent in doing their job of damaging the cancer cells without affecting healthy cells.

Cancer Treatments: A New Approach

In an exclusive interview with Decoded Science, Dr. Stojdl explained:

The idea of “tricking” cancer cells into committing suicide is an old idea and a common theme in chemotherapy.  In fact most current chemotherapies work by causing damage to our DNA or its duplication machinery which ultimately end up activating an “apoptosis” pathway to kill the cell.  What is different with the approach that we have outlined is how this death pathway gets setup.  In our novel combination strategy, we mildly stress the tumour cell by increasing the unfold protein burden temporarily which tricks the cell into “readying” a backup plan of cell suicide.  A key difference from current chemo is that the act of stressing the cell to “ready” a death response in the way we have described is in itself not toxic. In fact, it is not until the oncolytic virus infects the tumour that this backup plan put into action to trigger the cell death. Since the virus is very tumour selective on its own and the sensitizing stress itself is mild, this potent combination strategy could eliminate many of the toxic side effects that currently limit the effectiveness of current chemotherapy.”

Significance of This Cancer Treatment

RNAi Process Image by Richard Robinson

These findings offer a promising solution to cancer that is resistant to conventional therapies, like chemotherapy and radiation therapy. RNAi-based therapies are currently being tested for various forms of cancer by several pharmaceutical companies in the hope of finding better solutions to beat the disease. These are also being tested in combination with chemotherapy and radiotherapy which seem to work synergistically.

Dr . Stojdl emphasizes that the results of their research show that oncolytic virus therapy can be improved not just by improving the virus, but also by conditioning the patient’s tumor to be more susceptible.  He says, “The main point of the study was that the power of genome scale studies using robotic RNAi screens could be brought to bare for biological therapies against cancer and that completely unforeseen opportunities for more effective therapies could be uncovered.”  He thinks that this represents a blueprint for the future development of oncolytic virus therapy, and that the challenge now is to get these tested in human clinical trials.

The Future of RNAi

When asked about the potential for human cancer therapy,  Dr. Stojdl informed us that so far the strategy has been found to be effective in breast cancer and ovarian cancer in animal models.  They have also successfully tested a large panel of human cancer cell lines including brain, prostate, bone and lung, indicating that this may be a fairly wide spread phenomenon among cancers. Furthermore, this strategy has been shown to work with a new rhabdovirus virus-based oncolytic virus that is scheduled to go into early phase clinical trials within the next 18 months.  However, this combination therapy will have to wait for the development of a new medicine, since ccording to Dr Stojdl, the drug used in this study ” is not potent enough to test in patients and will need several years of refinement before it can be tested in humans.”

References

David F. Stojdl et al. Virus-Tumor Interactome Screen Reveals ER Stress Response Can Reprogram Resistant Cancers for Oncolytic Virus-Triggered Caspase-2 Cell Death. Cancer Cell. (2011). 20 (4): 443 DOI: 10.1016/j.ccr.2011.09.005. Accessed December 9, 2011.

National Institute of General Medical Sciences. RNA Interference Fact Sheet. Accessed December 9, 2011.

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