New research on mice shows that drug-resistant melanoma tumors shrink when treatment is interrupted, or given a “holiday”, suggesting that altering the dose pattern of cancer drug treatment in this manner could be a simple way to extend survival in human patients with late-stage disease. However, only human trials can verify if this is the case.
The researchers, from the Novartis Institutes for Biomedical Research (NIBR), and the University of California – San Francisco (UCSF), both in the US, together with a team from the University Hospital Zurich in Switzerland, report their study in the 9 January online issue of Nature.
Co-lead researcher Martin McMahon, a cancer biologist at UCSF, and colleagues, found that one mechanism by which melanoma cancer cells become resistant to the anti-cancer drug vemurafenib (brand name Zelboraf), also makes them become addicted to it.
The consequence of this simultaneous resistance-cum-addiction to vemurafenib is that the cancer cells then proceed to use the compound to boost the growth of deadly, fast growing, drug-resistant tumors.
Once they made this discovery the team proceeded to experiment with changing patterns of drug dosage to see what effect this might have on mice implanted with melanoma tumors.
They found an “on-off” dosage pattern of treatment extended the lives of the mice, as McMahon, Efim Guzik Distinguished Professor of Cancer Biology in the UCSF Helen Diller Family Comprehensive Cancer Center, explains in a statement:
“Remarkably, intermittent dosing with vemurafenib prolonged the lives of mice with drug-resistant melanoma tumors.”
The researchers suggest a similar approach might enhance the effectiveness of the drug in human patients and thereby extend their survival. The only way to show if this is the case is to test the method in clinical trials.
Melanoma is the deadliest form of skin cancer. Figures from the National Cancer Institute show over 76,000 Americans were diagnosed with the disease in 2012 and over 9,000 died of it.
As with all cancers, it starts when cells accumulate mutations in their genes which eventually makes them grow abnormally and then travel to other sites in the body. A common mutation in melanoma, which affects half of all people with the disease, is in the BRAF gene.
Vemurafenib was developed to treat patients with late-stage melanomas with mutations in BRAF. The US Food and Drug Administration approved it in 2011 after reviewing trial evidence that it significantly prolonged survival.
Unfortunately, although Vemurafenib causes the tumors to shrink at first, most patients who receive the drug experience a return of a lethal, drug-resistant form of the skin cancer.
“Vemurafenib has revolutionized treatment of a specific subset of melanoma expressing mutated BRAF, but its long-term effectiveness is diminished by the development of drug resistance,” says McMahon.
Experiments on mice implanted with melanoma tumors show a similar response to the drug: at first the tumors shrink, but eventually they re-emerge in a deadlier, more resistant form.
McMahon and colleagues worked with these same mouse models to see if they could pinpoint the underlying mechanism of drug resistance in the melanoma tumors.
They found that when melanoma cells encounter vemurafenib, they produce more BRAF protein. Thus the effect of the drug, which is to target BRAF, is to produce more of the protein. This is how the resistance develops.
It was this very discovery that led the team to wonder what might happen if they interrupted the dosing of vemurafenib. What if, the melanoma cells were not only becoming resistant to the drug, but also becoming “addicted” to it?
They postulated that removing the drug would therefore cause the tumors to shrink. And that is exactly what they saw.
When they stopped giving the drug to the mice with recurring, resistant tumors, the tumors shrank again, like they did before resistance set in.
Mice that continued to receive the drug, without interruption, died within 100 days or so. Mice that were treated with the same drug, but with regular interruptions in the dose, so-called “drug holidays”, all lived longer than 100 days.
McMahon notes: “By seeking to understand the mechanisms of drug resistance, we have also found a way to enhance the durability of the drug response via intermittent dosing.”
In another breakthrough study reported recently, researchers in Japan discovered it is possible to make cancer-specific immune system cells from induced pluripotent stem cells and use them to treat a type of skin cancer.
Written by Catharine Paddock PhD