Doctors could soon be able to mix and match anti-cancer drugs, in order to arrive at the ideal combination for attacking a particular tumour, following research1 published today.
Cancer Research UK scientists in Birmingham have gained detailed information about exactly how treatments send cancer cells to their deaths. They believe that choosing drugs that are complementary to each other – attacking cancer cells in different ways – should be an effective means of preventing tumours from becoming resistant to treatment.
They also managed to restore sensitivity to cancer cells that had already developed resistance – by infecting them with a modified virus carrying a powerful suicide message.
Anti-cancer drugs work by flicking a suicide switch within each cancer cell, with resistance developing when one such switch becomes jammed. But the new study reveals that the particular switch targeted varies from drug to drug.
Researchers focussed on ovarian cancer, which often initially responds to chemotherapy, only to later develop resistance against it. They removed cells from ovarian tumours, grew them in the laboratory, and treated them with a range of anti-cancer drugs. After each treatment they measured the levels and activity of a number of molecules that are involved in cell death.
Depending on the drug used, they detected activation of different cell death molecules, indicating that different suicide switches were being flicked. And they found that some drugs were working through an as-yet-unknown switch.
Researchers had previously thought that pushing cells to suicide required the presence of a cell death molecule called FADD. But while some drugs, such as fluorouracil and paclitaxel, were more effective in the presence of this molecule, others, including cisplatin and vincristine, were at least as effective in its absence. Understanding more about this new cell death mechanism could help in the future development of anti-cancer drugs.
Scientists hope that choosing drugs to target several different switches all at once could prevent a tumour from developing resistance to treatment.
Team leader Prof Lawrence Young, of Cancer Research UK’s Institute for Cancer Studies at Birmingham University, explains: “If a tumour is treated with just one drug, or with several drugs that all work through the same suicide switch, then it only takes that one switch to become jammed for the cancer to become completely resistant.
“But if we instead treat a tumour with several anti-cancer drugs, each of which targets a different switch, then the chance of the tumour becoming resistant to all the drugs at once is far smaller.
“Our research has allowed us to find out which switches are targeted by different drugs, so that we can learn to mix and match far more effectively than is currently possible.”
Prof Young and his colleagues also believe that finding out more about how drugs cause cancer cells to commit suicide could pave the way for new types of treatment. They found that treating drug-resistant cancer cells with cell death molecules seemed to re-activate suicide switches that had become jammed, restoring sensitivity to chemotherapy.
One cell death molecule which triggers a number of suicide switches is called CD95L. Researchers inserted this into a virus, which they then used to infect drug-resistant cancer cells. CD95L effectively short-circuited the cells’ jammed suicide switches, knocking them into suicide mode even though some of the switches had not been flicked.
Prof Young adds: “Suicide switches seem to work by setting off a series of death molecules, which end up killing the cell. In the future, it might be possible to directly treat cancer cells with these death molecules, effectively using them as anti-cancer drugs.”
Prof Gordon McVie, Joint Director General of Cancer Research UK, says: “Prof Young’s research could have a double benefit for cancer patients. It should allow doctors to make much better use of existing drugs, by using them in the combinations in which they’ll be most effective. And it may also lead to a new breed of drugs that work differently from conventional chemotherapy.”
Sir Paul Nurse, Joint Director General of Cancer Research UK, says: “The processes that go on during the death of a cancer cell are extremely complex and have never been fully understood. But the more we know about these processes, the better we will able to manipulate them in cancer cells that seem resistant to dying.”
- Cell Death and Differentiation9 (3) pp.287-300