Discovery by McMaster team provides key for targeted cancer treatment
A REASON WHY CERTAIN DRUGS work for some cancer patients but not others has been identified by a team of McMaster University researchers.
The discovery means doctors can immediately start targeting therapy so patients get the drug most likely to work for them and don’t waste precious time on treatment guaranteed to fail.
“We just have to give the right drug to the right patients, and the only way to connect the two is to understand how the drugs work,” said Dr. Mick Bhatia, principal investigator of the study and scientific director of the McMaster Stem Cell and Cancer Research Institute.
“These drugs have been around for years. They worked in some people and not in others but we didn’t know why.”
The answer is a protein in cancer stem cells that some people have and others don’t.
Bhatia explains that the stem cells are thought to be the root cause of cancer and drugs are used to kill them. But the drugs rely on a protein called Sam68. When that protein is absent, the drugs don’t work.
“It starts to explain a big problem in cancer therapy which is that not all patients respond,” said Bhatia. “You take a drug and half of them respond and half of them don’t, and we haven’t really been able to figure this
“It starts to explain a big problem in cancer therapy which is that not all patients respond.” DR. MICK BHATIA SCIENTIFIC DIRECTOR, MCMASTER STEM CELL AND CANCER RESEARCH INSTITUTE
out … What this showed us was that this protein not only helps the drugs work but it means we now have an explanation as to why for certain patients who took the drug it didn’t have an effect on them. It turns out it’s because they didn’t have the protein.”
While it sounds simple, the discovery published June 22 in the scientific journal Cell Chemical Biology was four years in the making.
“It took a lot of detective work,” said Bhatia. “Every month you don’t know if you are ever going to get an answer. You just keep pursuing.”
It was a keen eye that unexpectedly put the team on the right path to discovery. They had actually been researching something different altogether when unanticipated results made the team change direction.
Originally, they had been trying to figure out how cancer cells die when drugs attack the pathway allowing them to survive and grow. Considerable effort and billions of dollars have been spent by pharmaceutical companies around the world in the quest to turn off the Wnt pathway to stop cancer in its tracks.
“We know the drugs inhibit the Wnt pathway and we were using them to basically see how these cells were dying,” said Bhatia. “In that process we realized that not all patient cells die. You would have predicted if you inhibit that pathway, all the cells should die. But that is not the case.”
The team started dividing the cells that died from those that didn’t. They studied what separated the two groups with funding from the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Canada Research Chairs Program, the Fonds de Recherche en Sante du Quebec, and the Cancer Research Society.
“Why did this dish respond with these cells and these cells in the other dish not respond,” said Bhatia. “It was only when we started doing that side by side comparison that we started saying, ‘What is the difference?’ Luckily, we came out with something that gave us an answer.”
But finding Sam68 wasn’t enough. The team next had to prove the protein was the reason the drugs sometimes worked and sometimes didn’t.
“The way we do that is you mutate the protein,” said Bhatia. “If I change the protein, do I lose the drug response? And that was true.”
The study looked at two drugs used to treat leukemia, colon cancer and breast cancer. But they predict this finding will be the same for countless other drugs used to treat other cancers.
Their next step is to screen thousands of drugs to identify which require this protein to be present in the cancer cells to work.
“You are always looking for discovery — trying to find new drugs — but we actually think sometimes discovering how existing drugs work is important,” said Bhatia. “It’s not like we discovered a drug and years from now it may go into the clinic. These are drugs that are already in the clinic and it’s applying the knowledge to be more precise.”
Knowing which drugs require the protein and which don’t has the potential to make a profound difference for patients.
“We can say you have the greatest chance now of responding to these types of drugs because you’ve got this protein,” said Bhatia. “If you don’t have this protein, then this isn’t the therapy for you. You’re better off to go to an alternative because the longer you have the cancer growing, the worse it is.”
The team will also start looking at whether they can repeat this discovery by following similar steps to find why other drugs only work on some patients.
“It’s possible there are a lot of drugs out there that work quite effectively we just don’t know exactly how they work,” said Bhatia. “Connect those dots and get the drug to the right patient.”
Post-doctoral fellow and first author of the study Yannick Benoit (left) works with trainee Justin Lu in the McMaster Stem Cell and Cancer Research Institute. The McMaster team’s study means cancer patients can get the drugs most likely to work for them.