Team grant enables crucial, large-scale clinical trial to help children recover from brain cancer 

By Alison Palmer, Evaluation and Special Projects Lead, Brain Canada

A pilot project funded through a W. Garfield Weston Foundation – Brain Canada Multi-Investigator Research Initiative (MIRI) grant in 2012 proved the feasibility of repairing brain injuries in children caused by radiation treatment. Now, the team is running a phase three clinical trial to test the efficacy of repurposing metformin, a drug widely used to treat diabetes and metabolic disorders in children, at a larger scale to improve outcomes in children recovering from brain cancer.  

Tobin’s story 

At age two, Tobin was diagnosed with a rare brain tumour. He had two recurrences at age five and age nine. Throughout his young life, Tobin received a total of 63 radiation treatments to his brain, 20 cycles of chemotherapy, and three major and three minor brain surgeries at SickKids hospital.  

Now in his mid-twenties, Tobin is a registered nurse working to give back to the field that gave him so much. He did his practicum at SickKids, for example, a place that had become a second home. His road to recovery has not been without challenges; Tobin underwent open heart surgery three years ago, after being diagnosed with an ultra rare metastatic sarcoma that started in his heart.  

His mom, Karen Haas, is incredibly proud of her son’s resilience and accomplishments. She is also incredibly grateful.  

Given all that radiation he received as a child for the initial and then for recurrences [of brain cancer], we know that it’s very significant that he is now an RN.

– Karen Haas, Tobin’s mother.

Karen is well aware of the lifelong side effects of all the treatment Tobin received. While often crucial to a patients’ survival, treatment for brain cancer can be highly toxic, with devastating effects on a developing brain. Survivors are known to have significant long-term medical conditions, including cognitive impairment, growth issues, early strokes, and hearing loss.  

The pilot clinical trial funded by Brain Canada sought to mitigate adverse effects of treatment. Specifically, Dr. Don Mabbott at The Hospital for Sick Children (SickKids) tested whether the diabetes drug metformin could promote cognitive recovery and repair in the injured – and developing – brain. The trial took basic research findings into the clinic, building on research by co-investigators Dr. Freda Miller on neural stem cells and Dr. Cindi Morshead on a rodent model.   

As a pre-teen, Tobin, eager to resume school, play baseball and hockey, and attend summer camp, had the opportunity to participate in this pilot trial along with 23 other survivors of pediatric brain tumors who had been treated with cranial radiation. 

What’s the impact?

The pilot trial was successful – the drug was safe and well-tolerated by the children who received it, and researchers saw an enhancement of brain repair and improvement on certain cognitive tasks in the short term after treatment.  

These results allowed the team to pursue the next step to impact – a large scale, phase three clinical trial. The trial, which is still recruiting, has 14 sites in Canada and four in Australia, with several additional sites in development in the United States. It is funded by the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society with an investment of $2.5 million, and an Australian grant of an $1 million Australian dollars. 

The MIRI grant from Brain Canada was leveraged to take the next step in the translational pathway, from pilot to phase three When people talk about team science, this is my go-to grant to highlight, because it really was a translational pipeline – from cellular, to molecular animal model, and then up to human studies. It was truly a multidisciplinary program of research, and I think that’s why it was so successful.

– Dr. Don Mabbott, The Hospital for Sick Children (SickKids)

Dr. Mabbott is involved in several additional trials that were catalyzed by the results of the Brain Canada-funded pilot project. The CHILD-BRIGHT network trial, funded through CIHR’s Strategy for Patient-Oriented Research (SPOR) and others, is evaluating whether metformin combined with physiotherapy enhances motor and thinking skills in children with cerebral palsy. The Multiple Sclerosis (MS) Society of Canada is supporting a trial testing whether metformin can repair damaged white matter in youth and young adults with MS.

Did metformin contribute to Tobin’s successful outcome? 

“We’ll never know, of course, if it did have that effect,” Karen explains. These kinds of trials, which test the feasibility of a drug at a population level compared to a placebo, don’t investigate individual outcomes. But Karen does admit that their involvement changed their lives. It is also changing the way this research is conducted. 

Karen and Tobin were involved with the funding application for the phase three trial from the outset, and Karen helped to develop the Stakeholder Engagement Committee, which she Chairs. Tobin is a member of this Committee as well. Their role is to support recruitment, share insights about the experience of people participating in these important trials, and ease the burden on patients and families as much as possible. 

“Tobin contributes a very unique perspective – he knows what it’s like to be that young person taking the pills and doing the various tests,” explains Karen Haas. “Now that he’s a young adult, he can articulate more than when he was a child participating in the research, he can share the little issues that he had and help make it a better experience for families coming later.”

In addition to her involvement with the phase three trial, Karen is the Family Chair of the Research Family Advisory Committee at The Hospital for Sick Children. She also served on the Research Ethics Board in Ontario for six years. Dr. Mabbott describes Karen as “an excellent, excellent resource.” 

“Being involved in this larger trial from the grant writing phase is really significant,” Karen says. “I actually think it’s the way research should be done – involving patient partners from the start.” 

Learn More

Listen to the SickKids VS podcast Can we heal the brain? to learn more: “This is a story about a group of scientists who are asking one of the biggest questions out there: can we heal the brain? And about one family working with them who has a big stake in the answer.” 

In 2012, Dr. Donald Mabbott, Senior Scientist in Neurosciences and Mental Health at The Hospital for Sick Children, along with co-investigators Dr. Freda Miller, Dr. Cindi Morshead, and Dr. Paul Frankland, received a $1.5 million research grant from the W. Garfield Weston Foundation – Brain Canada Multi-Investigator Research Initiative (MIRI) Grants competition. The multidisciplinary team confirmed that metformin, a type 2 diabetes drug that was known to activate the same pathway they had discovered in neural stem cells, enhances the genesis of brain cells and in doing so, promotes brain repair in the injured brain. To enhance the translational potential of their research, the studies were conducted in both mice and humans, with a particular focus on brain repair in children. Read more on our website: Help for kids with injured brains.