Turning Genetic Discovery Into Actionable Therapies for Children With Cancer

For more than a decade, Canada has been at the forefront of sequencing childhood cancers, unlocking detailed genetic and molecular insights into some of the most complex diseases. But for many families, those insights have come with a difficult reality – knowing more about a tumor does not always mean being able to treat it.

“This has been a missing piece,” said Daniel Morgenstern, Head of Clinical Trials, The Hospital for Sick Children and Co-Lead, Clinical Trials, ACCESS. “We’ve had the ability to identify potentially targetable mutations for years – the challenge has been having clinical trials available to act on those findings.”

ACCESS’ national precision oncology driver project, PROFYLE, has made it possible to analyze both the DNA and RNA of tumors from children with hard-to-cure cancers. These efforts generate vast amounts of data that need to be interpreted to identify biological pathways that can be targeted with drugs. But without clinical trials that provide access to the new therapeutics that target these pathways, the molecular discoveries often stop short of impacting patient care.

“We’ve actually gotten very good at deciphering what’s happening in a tumor,” said Rebecca Deyell, Pediatric Hematologist-Oncologist, BC Children’s Hospital and Co-Lead, Clinical Trials, ACCESS. “The real gap is being able to use that information to treat patients with actionable therapies”. Now an ACCESS-supported clinical trial, OPTIMISE, bridges that gap by directly linking sequencing results to treatment options.

Unlike traditional trials that test one drug in one group of patients, OPTIMISE operates as a platform trial. Using a single master protocol, it allows multiple therapies to be tested at once, assigning patients to treatment pathways based on the molecular features of their tumor. “It’s much more efficient,” explained Daniel Morganstern, who acts as Canadian chair of the OPTIMISE study. “Instead of opening a new study every time, we can add new treatment pathways as amendments.” This flexibility is critical in pediatric oncology, where resources and time are limited.

Beyond individual treatments, OPTIMISE creates a national infrastructure for pediatric precision oncology trials. Instead of building studies from scratch, new therapies can be added into an existing system – making it faster and more attractive for partners. “One of the biggest challenges has been convincing industry that we can run these studies efficiently. Having this platform in Canada changes that conversation,” shared Rebecca. “With patient support programs and increasing options for decentralized monitoring, we are able to recruit from across the country in hopes of making access more equitable across our huge geography.”

OPTIMISE also broadens how precision medicine is defined. While many approaches focus on DNA mutations, this trial incorporates tumour RNA profiling to understand how genes are actively expressed. In one arm, researchers identify “immune hot” tumors – those rich in immune cells – which may respond better to immunotherapy. “We’re using RNA data to predict which patients might benefit from immune checkpoint inhibitors,” Rebecca said. “If you treat unselected cases, response rates are low – but there are rare cases where patients respond really well. The goal is to identify those patients upfront and improve outcomes while avoiding unnecessary treatments.”

Canada’s participation in the OPTIMISE clinical trial was made possible through the partnership and collaboration of multiple organisations, institutions and individuals in Canada – and crucially, in Australia. “Canada and Australia are in a similar position,” added Daniel. “We’re not the U.S., and we’re not Europe, where most trials happen.” By collaborating, both countries can recruit enough patients to run meaningful studies and expand access to novel therapies.

David Ziegler, Director of Clinical Trials, Sydney Children’s Hospital and KOALA, and Australian Chair of OPTIMISE, emphasized the importance of this approach. “Programs like OPTIMISE represent the next step in precision oncology – where genomic insights are not just generated but systematically linked to clinical trials. International collaboration is essential if we want to deliver truly personalized therapies to children, regardless of where they live.”

Additionally, the trial prioritizes patient experience. It includes patient-reported outcomes, allowing families to share how treatments affect them directly. “It’s incredibly valuable; what patients feel doesn’t always match what clinicians record”, added Rebecca.

At its core, OPTIMISE speaks to the missions of both ACCESS and ANZCHOG (the Australian/New Zealand Childhood Haematology and Oncology Group). By linking discovery to treatment, OPTIMISE completes the precision medicine pathway, from sequencing, to insight, to care. Still in its early stages, the platform is designed to evolve over time, continuously adding new therapies and expanding options for children with relapsed or hard-to-treat cancers. “For kids with relapsed cancer, just having another option is meaningful,” David Ziegler said

In a field where progress is often incremental, OPTIMISE represents a structural shift, one that brings scientific discovery closer to real-world impact, and ultimately, hope for kids with cancer.

The OPTIMISE trial has been made possible with the vital support of the Cancer Research Society, Stand Up 2 Cancer, Canadian Institutes of Health Research, ACCESS, and the Australian Medical Research Future Fund. The study is sponsored globally by ANZCHOG, with C17 Council providing regulatory coordination for Canada.