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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.
The problem:
One of the factors that make cancer so hard to treat is that it can evolve to become resistant to a treatment. Cancer cells mutate frequently by their very nature. A drug might initially be very effective at killing them, but if a few cells happen to have developed a mutation conferring resistance against that drug, they will survive, multiply, and eventually come to represent the majority of cells within the tumour. But what if we could use this ability to evolve to our own advantage, ‘cultivating’ a tumour to include cells with a certain vulnerability, then taking them all out at once? That’s precisely what researchers attempted to do in this study.
The discovery:
In this study, researchers introduced two genes into cancer cells. The first gene conferred resistance against a cancer drug, while the second was a ‘kill switch’ that, when activated by the administration of another drug, would cause the cancer cells to self-destruct in a manner that also killed nearby cancer cells. Such genetically engineered ‘kill-switches’ are very effective at killing cancer cells, but their utility as a treatment is limited because the viral vectors that carry them can only infect a fraction of the cancer cells within the tumour.
In this study, since the kill switch was introduced alongside a gene conferring drug resistance, researchers were able to use said drug to apply a selective pressure. Cells lacking the kill switch were outcompeted by the engineered cells until the majority of cells within the tumour carried the kill switch, alongside unmodified cells that had evolved drug resistance. Scientists could then activate the kill switch to wipe out all engineered cells at once, also killing nearby unmodified cells in the process.
After optimising this treatment in vitro, the researchers tested this technique in mice given human lung cancer cells. Some drug-resistant cells were included and 10% of cells were modified with the kill switch treatment. In the control group of 10 mice lacking genetically modified cells and given only the anti-cancer treatment osimertinib, tumours initially shrunk but returned when cells developed resistance, leading to the deaths of all 10 mice. Yet in the group of 12 mice that received the kill switch treatment, only a single mouse died.
The implications:
This study suggests that we may be able to use the rapid evolution that occurs within cancers to our advantage, engineering them to be more responsive to therapies that normally struggle to eliminate the cancer entirely. The mouse studies done here are not entirely representative of how this treatment would work in humans, as the mice were given cancers already containing genetically modified cells. In humans, genetic alterations would have to be introduced via some kind of vector, which introduces some barriers, such as needing to ensure that the vector targets the right tissue and reaches a sufficient number of cells. That said, the authors suggest that the therapy would not need to reach many cells within the tumour, since the point of this approach is to amplify their numbers through natural selection. So long as the number of cells bearing the drug resistance plus kill switch combination outnumbered the starting population of naturally drug-resistant cells (which is typically very low), the kill switch-bearing cells should come to represent the main population of cancer cells following drug therapy.
Programming tumor evolution with selection gene drives to proactively combat drug resistance https://doi.org/10.1038/s41587-024-02271-7
Title image by kjpargeter on Freepik
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