Dis­cov­ery by McMaster team pro­vides key for tar­geted cancer treat­ment

The Hamilton Spectator - - FRONT PAGE - JOANNA FRKETICH

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.”

COUR­TESY, MCMASTER UNIVER­SITY

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.

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