This project is game-changing because studying GBM after standard treatments is extremely difficult due to the rarity and spread of surviving tumour cells throughout the brain. By developing an advanced MRD lab model using patient tumour samples, the Parrinello lab can study these resilient cells without needing risky biopsies. This model will provide a deep understanding of how GBM cells resist treatment and regrow.

By developing advanced laboratory models that mimic how current treatments for GBM leave behind resilient tumour cells that quickly regrow, this project will enable us to understand the weaknesses of these surviving cells in unprecedented detail. This insight can help create new methods to eliminate these residual cells or make them more responsive to existing treatments, preventing their regrowth into aggressive recurrent tumours. This advanced MRD model will also be used to test new therapies and facilitate personalized drug screening. Ultimately, this could lead to more effective treatments and improved survival rates for GBM patients.

Current standard-of-care treatments for GBM, which include surgical resection, temozolomide chemotherapy, and radiation therapy, fail to prevent rapid tumour recurrence. The persistence of therapy-resistant tumour cells, which invade beyond the resection margin, results in a median survival of less than 15 months. This project aims to develop an ex vivo model of minimal residual disease (MRD) to elucidate the biological vulnerabilities of these residual GBM cells. By leveraging primary and organotypic culture models, mass cytometry, and extensive molecular profiling, this will lead to unprecedented insights into the resistance mechanisms of MRD. This model will serve as a functional test bed for novel therapeutic strategies and facilitate personalized drug screening. The project will also explore the transient cellular states induced by standard-of-care treatment, offering tumour-selective therapeutic opportunities to target these resilient cells to prevent tumour re-growth. Ultimately, this research could lead to more effective, biologically-informed therapies and improved patient outcomes.

The overarching aims of this grant includes:

Aim 1. Develop a model of human GBM residual disease.

Aim 2. Develop a molecular profiling pipeline of resistance mechanisms within residual cells.