The little girl with the pink glasses and the blue sweatshirt is smiling with a photo on the wall. It hangs in Tamra Werbowetski-Ogilvie’s sixth-floor office, overlooking the treetops of the neighborhood surrounding UM’s Bannatyne campus.
Next to the framed photo are pictures of his two children, including his daughter. He is about the same age as this young woman who was undergoing cancer treatment and who was connected to a foundation that funded Werbowetski-Ogilvie’s work on pediatric brain tumors, the deadliest of childhood cancers.
The Rady College of Health Sciences researcher recalls chatting with the inquisitive girl on a Zoom call a year ago.
“They’re emotional meetings, you know? And I can’t get through them without crying. She was so grateful when I met her and so happy that people were doing work,” says Werbowetski-Ogilvie. “It’s your turn. You see? I’m already getting excited.”
That’s why she chose life as a stem cell biologist instead of a doctor. Pediatric brain cancer became an obvious choice; it is a discipline hungry for discovery. This cancer is surprisingly rare in children; it has only been in the last decade that research in this specialist field has gained momentum, with advances in gene sequencing technology. But even so, childhood cancers in general are “ridiculously underreported,” Werbowetski-Ogilvie is quick to point out. “In the States, they account for less than four percent of all funded cancer research. And it’s the same everywhere.”
Approximately 1,000 children are diagnosed with cancer in Canada each year, including about 50 in Manitoba. About 10 of these children will learn that they have a malignant tumor in their still-developing brain. Some of them will be diagnosed with a medulloblastoma tumor, the type Werbowetski-Ogilvie is researching.
“Parents don’t care how rare it is. They want to find better treatments.”
He says this just weeks before the prestigious journal Nature publishes what may be his team’s most important results to date. With collaborators in Toronto, Seattle and Tokyo, they identified how and where aggressive types of medulloblastoma, in pre-malignant form, first appear during the development of a child’s brain, while it is still in the womb. uterus Children are not usually diagnosed with this type of tumor, known as group 4, until the age of seven, suggesting that there is a window of several years to prevent the cancer from developing.
Until now, group 4 tumors were the least known, but require one of the most intensive treatments. Up to 40% of children do not survive.
Parents don’t care how rare it is. They want to seek better treatments.
With new clarity about which genes go awry and grow into tumors, doctors could spot these problematic cells before they turn into cancer; it is the first time scientists have suggested that medulloblastoma can be prevented. Now they can also develop better models of human cells to test potential drugs to slow or stop their spread.
“With better models, we can actually make progress,” says Werbowetski-Ogilvie.
Brain cancer, he reiterates, does not always reach the spotlight. Greater attention tends to unravel the mysteries of leukemia, which affects the blood and is the most common cancer among children.
“In leukemias, better progress seems to have been made in terms of survival rates. Whereas with brain tumors, especially for these very, very bad cases, current therapies don’t really extend life beyond a couple of extra months and are so toxic,” he says. “We have to do better with brain tumors. And I think we’re definitely moving in that direction.”
The search for new treatments finds fuel in the biology of cancer stem cells, where scientists identify the “cellular fingerprint” of a tumor.
“We’re looking for the proteins on the surface of a cell and inside the cell that make these tumors unique,” says Werbowetski-Ogilvie. “And then we look for drugs that target that unique signature.” In this way, oncologists can go after diseased cells while leaving the surrounding healthy cells intact.
This shift in focus will redefine the future of cancer care by offering alternatives to radiation and chemotherapy, which simply go after all dividing cells, healthy or not, he explains. A more personalized approach is particularly overdue for children, who suffer worse long-term side effects than conventional options.
“The tests and drugs for children can’t be lumped into what’s given to adults. They’re not the same. Everything we know about childhood cancer is different: the mutations, the drugs they’ll respond to, how they’ll respond. We’re dealing with developing bodies, right? And so we have to think about how we treat these diseases in very different ways.”
“This is where I need to be,” says Tamra Werbowetski-Ogilvie, who held a Canada Research Chair in neuro-oncology and human stem cells for a decade.
She and her mostly female team, many of whom are mothers of young children, have spent years researching another type of medulloblastoma, the sonic hedgehog brain tumor, which originates in the cerebellum. It was Harvard Medical School postdoctoral fellow Robert Riddle who first identified the protein behind tumor growth. The protein belongs to the hedgehog genes. (Riddle raised eyebrows when he called him a “sonic hedgehog” after the 1990s Sega video game character.)
Werbowetski-Ogilvie set out to discover a drug that would target this cancer, and in 2018, she discovered that selumetinib slowed tumor growth, just as her hypothesis expected. But stopping the study there, notes Werbowetski-Ogilvie, would have been like plucking a dandelion from the surface rather than removing the root. So they looked for the possibility of a second drug, and serendipity intervened.
If the 2020 COVID-19 shutdowns hadn’t shut down his lab, those experiments wouldn’t have been interrupted, and his team wouldn’t have collected data at the precise point that alerted them to the rapidity, not one, but a combination of the drugs (selumetinib, along with pacritinib) reduced these tumors. “One model showed an almost 90% reduction in tumor growth. Over time, this translated into an increase in survival of more than 40%,” he says. “You can feel the excitement in the lab when a story comes together and everything clicks.”
Postdoctoral student Jamie Zagozewski [BSc(Hons)/09, MSc/12] he remembers that moment well. “We were blown away when we saw how much we could reduce the overall size of these tumors,” says Zagozewski, 37. “These parents are going through what I imagine is the worst time of their lives, and if I can have anything to do with helping to alleviate that, that’s amazing.”
Until then, none of these drugs had been tested in medulloblastoma, but because they have been used in other childhood cancers, approvals may come more quickly, Werbowetski-Ogilvie says.
“I don’t like hearing the term ‘Good enough,'” he says. “You have to keep at it and you have to keep trying. Best effort.”
Biochemistry and Medical Genetics Professor Tamra Werbowetski-Ogilvie grew up in Thunder Bay, Ontario, changing diapers for daycare at her mother’s house and enjoying being around children and their curiosity. His father, a petrographic technician who worked on asphalt and was known as “the rock doctor,” would help him with his science projects with a reference topic of, what else?, erosion. From there, he developed a passion for solving problems.
Finding new ways to treat brain cancer is particularly complex, as drug candidates must effectively reach tumors in this delicate organ. Many drugs are designed not to affect the brain, not to cross our blood-brain barrier, which protects toxins from entering. Finding new and tailored treatments is even more complicated as there are many different types of tumours: 120 to be exact. , according to the Brain Tumor Foundation of Canada.
Fortunately, in recent years, more affordable sequencing technology and the effort of the international research community to catalog the genetic differences between these tumors means that scientists have a breakdown of the genes involved in all forms of medulloblastoma. While this is very useful, the data does not speak to the behavior of these genes and how they affect individual cells. It can be overwhelming trying to figure out which one to focus on, admits Werbowetski-Ogilvie.
“When we get these big data sets, our job is to figure out which of these genes or proteins end up being functionally relevant. Not all of them are,” he says. “It takes years to prioritize what to work on and figure out what our genes of interest actually do.”
In Werbowetski-Ogilvie’s office, on her whiteboard, are her son’s old scribbles that have been there so long they won’t erase. On his shelf is an anatomical model of a brain and a “science lab” that his daughter made from a drawing of milk, along with a drawing she made of the mother as Wonder Woman, which the his team placed prominently during a surprise makeover of the space. .
“What I teach in my lab and what I teach my kids is perseverance,” he says. “With science, sometimes the experiments don’t work, but you have to keep going.”
That’s not lost on Zagozewski, who says it’s no small feat to be part of a predominantly female team in a STEM field, led by a researcher who is both tenacious and encouraging. “We’re not just scientists, we’re friends and mothers, we all support each other,” she says. “It’s not just a job, it’s more than that.”
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