The Pan-Canadian Lower-grade Glioma (MOH-PCLG) project: Enabling biomarker-driven treatment options for relapsed IDH-mutant gliomas

Abstract Canada network map

Unravelling the evolutionary biology of IDH-mutant gliomas to improve treatment options for relapsed patients

Outcomes for patients with certain cancer types have seen encouraging improvements in recent decades. Unfortunately, this is not the case for many patients with diffuse gliomas, the most common type of primary brain tumours. While substantial strides have been made in the upfront treatment of lower-grade gliomas (defined as those of grades 2 and 3), at relapse they are very resistant to treatment and behave aggressively. 

This is in part due to the complexity and heterogeneity of these cancers, which contributes to treatment resistance. Even though they may initially respond to treatment – which usually consists of surgery, radiation, and chemotherapy – the tumours almost inevitably return. 

Diffuse gliomas can be separated into two broad categories: lower-grade gliomas (which are sometimes referred to as IDH-mutant gliomas because they almost always carry a mutation in the IDH1 or IDH2 gene) and glioblastomas. Although lower-grade gliomas usually respond better to initial treatment than their more common glioblastoma counterparts, they remain incurable. When lower-grade glioma patients do eventually relapse, their treatment options are extremely limited and, for some types, median survival is as low as 10 months. 

"There is a critical need for a greater understanding of how recurrence occurs in low-grade glioma patients, and for more therapeutic options for these patients,” says Dr. Jennifer Chan, a neuropathologist and Director of the Arnie Charbonneau Cancer Institute at the University of Calgary. 

To address these gaps, Dr. Chan leading a team of researchers from Alberta, Manitoba, British Columbia, Nova Scotia, and New Brunswick working on the Pan-Canadian Lower-grade Glioma (MOH-PCLG) project. This work is being funded by the Marathon of Hope Cancer Centres Network (MOHCCN)'s Pan-Canadian Projects program, and data generated through the project will also be contributed to the MOHCCN Gold Cohort to facilitate additional future studies. 

One of the project goals is to better understand how low-grade gliomas evolve in response to therapy and how this impacts the biology of relapsed tumours. To do this, researchers will perform molecular profiling – such as DNA and RNA sequencing – of paired initial and recurrent tumours from the same patient. This will allow them to compare the biological characteristics of tumour cells before and after treatment.  

“Understanding how lower-grade gliomas evolve over the course of therapy, from response to resistance, is crucial to developing better strategies to treat these cancers," explains Dr. Chan. “Existing longitudinal data is limited in this cancer type. We aim to create one of the largest cohorts of lower-grade gliomas globally, and the only one fully characterized with DNA and RNA sequencing as well as clinical annotations. This resource will significantly advance our collective knowledge of this disease, catalyzing innovation and therapeutic developments.” 

Another goal of the study is to support a multi-centre clinical trial for recurrent lower-grade gliomas. The Low & Anaplastic Grade Glioma Umbrella Study of MOlecular-Guided TherapieS 2 (LUMOS2) trial is a phase II trial that aims to match recurrent lower-grade glioma patients with precision therapies based on their tumour's molecular characteristics. 

Patients eligible to participate in this trial will be approached to see if they also wish to participate in the MOH-PCLG project. Molecular profiles of the participating patients’ tumours will be generated and used to match patients to the most appropriate arm of the LUMOS2 trial. 

The Canadian arm of the LUMOS2 is led by Dr. Marshall Pitz, co-Chair of the Brain Disease Site Committee of the Canadian Cancer Trials group, medical oncologist at CancerCare Manitoba, and co-lead of the MOH-PCLG project with Dr. Chan. 

"This project will build a framework for discovery and translational research in the lower-grade glioma space and will also provide detail about the mechanisms of response or resistance to the study treatments in the LUMOS2 clinical trial” says Dr. Pitz. “The data will provide an invaluable resource for understanding molecular evolution over time, contributing to the foundational knowledge needed to develop novel therapies, guide the selection of appropriate therapies, and improve care for patients with lower-grade gliomas.”