New way to combat drug resistance in skin cancer found

 

---

Vemurafenib doesn’t cure advanced melanoma. But it can prolong life by months, relieve the symptoms of the disease, and shows more clinical effect than almost every other treatment for advanced melanoma.

Rapid resistance to vemurafenib -- a treatment for a type of advanced melanoma, the deadliest form of skin cancer -- could be prevented by blocking a druggable family of proteins, according to research published in Nature Communications today.

Scientists at the Cancer Research UK Manchester Institute, based at the University of Manchester, have revealed the MLK family of four enzymes 'undoes' the tumour-shrinking effects of vemurafenib.

Around half of metastatic melanomas -- aggressive skin cancer that has spread to other parts of the body -- are caused by a fault in the cell-growth gene BRAF, causing the signal telling cells to multiply to be permanently switched on.

Vemurafenib blocks BRAF and stops the cancerous cells from growing. But cancer cells usually find a different way to turn the pathway back on -- cancelling out the drug's effects. Most metastatic melanoma patients stop responding to the drug within about six months, leading to a relapse of the disease.

This new research has found MLK enzymes can be responsible for reactivating the BRAF pathway, even in the presence of vemurafenib. By blocking these enzymes, which previous studies have shown is already possible, the researchers hope they can stop resistance to vemurafenib so the cancer cells are still vulnerable to the drug.

The findings also show that some melanoma patients have additional gene mutations that switch MLK genes on, causing patients to develop resistance to vemurafenib more quickly.

Lead author, Dr John Brognard, at Cancer Research UK Manchester Institute, said: "This exciting research reveals that melanoma cells have enzymes acting like a manual override switch to regenerate growth signals -- even after vemurafenib has switched them off.

"Additionally, this family of enzymes are turned on in metastatic melanomas that are not caused by BRAF, suggesting they may serve as a new target in metastatic melanomas for which there are limited treatment options.

"The good news is there are already experimental drugs that can block these enzymes in the laboratory. And this research paves the way for the development of drugs to overcome vemurafenib resistance in melanoma patients."

Professor Nic Jones, Cancer Research UK's chief scientist and director of the Manchester Cancer Research Centre, a partnership between CRUK, The University of Manchester and The Christie NHS Foundation Trust, said: "This exciting research opens new routes to treat this difficult disease. Thanks to people's generosity we've funded research that revealed that the BRAF gene is behind around half of all melanomas. And several drugs that target BRAF are now showing promise in clinical trials.

"Rates of melanoma in Britain are now five times higher than in the mid-1970s, but survival rates have also improved, with more than eight in 10 surviving for more than 10 years.

"We hope this latest research will lead to new treatments enabling even more people to beat this disease. Melanoma research is a key priority for the Manchester Cancer Research Centre."

---

Story Source:

The above story is based on materials provided by Cancer Research UK. Note: Materials may be edited for content and length.

---

Journal Reference:

1. Anna A. Marusiak, Zoe C. Edwards, Willy Hugo, Eleanor W. Trotter, Maria R. Girotti, Natalie L. Stephenson, Xiangju Kong, Michael G. Gartside, Shameem Fawdar, Andrew Hudson, Wolfgang Breitwieser, Nicholas K. Hayward, Richard Marais, Roger S. Lo, John Brognard. Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors. Nature Communications, 2014; 5 DOI: 10.1038/ncomms4901

Experimental Drug Shows Early Promise for Some Cases of Advanced Melanoma

 

 

TUESDAY April 8, 2014, 2014 -- An experimental cancer drug that activates the immune system has shown early promise for advanced cases of melanoma skin cancer, researchers report.

The findings come from an early stage trial of just 31 patients. But experts were cautiously optimistic about what the study showed: The drug's side effects were manageable, and four patients saw their tumors shrink.

That's a small number, but a trial like this is largely aimed at seeing whether a drug is safe and finding a tolerable dose.

"Any time you see some responders in an early study, it's encouraging," said Dr. Jeffrey Weber, a melanoma expert at the Moffitt Cancer Center in Florida, who was not involved in the research.

Much more remains to be learned about the drug -- known for now as IMCgp100. "But," Weber said, "it is good enough to show some activity in an early stage trial. It's definitely worth pursuing."

IMCgp100 is just one of several "immunotherapies" under study for advanced melanoma. The general idea behind immunotherapy is to help the body's immune system do a better job of recognizing and killing off cancer cells.

Melanoma is the rarest, but deadliest, form of skin cancer. Caught early, it's curable with surgery. But once it spreads to distant lymph nodes or other organs -- known as stage 4 melanoma -- the disease is very hard to treat.

In just the past few years, though, researchers have made headway. In 2011, the United States and Europe approved an immunotherapy drug called ipilimumab (Yervoy) -- the first treatment shown to prolong the lives of some patients with advanced melanoma.

Still, only a minority of patients respond to the drug, and it can cause severe side effects -- including life-threatening inflammation of the liver or digestive tract.

So there's an acute need for additional therapies, said Dr. Mark Middleton, who was to present the new findings on Tuesday at the annual meeting of the American Association for Cancer Research, in San Diego.

"The reality is, despite exciting advances in treatment, most of the patients we see with advanced melanoma will die of the disease," said Middleton, of Oxford University in England.

IMCgp100 targets melanoma in two ways: It attaches to a specific, tiny protein found on some melanoma cells, and it activates nearby T-cells to attack the tumor.

The catch is that a patient's cancer must be positive for that protein, called HLA A2 -- which is true in about 45 percent of melanomas, Middleton said.

The 31 patients in this study were all HLA A2-positive, and all but one had stage 4 melanoma. They were split into eight groups and given different doses of IMCgp100. Patients who were able to tolerate the first infusion received six more weekly treatments.

In the end, there were four patients who showed a "partial response" to the drug, which meant their tumors shrunk. One patient continued to see a regression with further treatment, and is still stable after more than 10 months, according to Middleton.

The most common side effects were rash, fever and "tumor flare" -- swelling and tenderness at the site of a tumor. Two of four patients who got the highest drug dose did have an immediate drop in blood pressure, so the researchers have since set the maximum dose below that.

Middleton said his team is now studying the drug in a larger group of patients, and trying to find the most effective regimen.

"The other obvious question is, where would this drug fit in?" Middleton said.

Besides Yervoy and other immunotherapies under development, there are also newer "targeted" drugs that directly attack proteins found on some melanomas -- including drugs called BRAF inhibitors.

Weber said researchers will have to figure out whether combinations of different therapies work better than a single one -- and which patients stand to benefit from a particular combination.

Middleton agreed. "We now have a whole range of therapies coming out, which is exciting," he said. But the difficult part, he added, will be understanding how to best use them.

In the United States, about 76,000 people will be diagnosed with melanoma this year, and 9,700 will die of the disease, according to the American Cancer Society. While melanoma is relatively uncommon, its incidence has been rising for the past few decades, the cancer society notes.

Immunocore, the company developing IMCgp100, funded the current study. Middleton reports no financial interests in the work.

The data and conclusions of research presented at medical meetings should be viewed as preliminary until published in a peer-reviewed journal.

More information

The American Cancer Society has more on melanoma treatments.