New Publication Offers Promising Treatment For Glioblastoma
The lab of MBP scientist Dr. Thomas Kislinger has assisted in the discovery of a new pathway used by cancer cells to infiltrate the brain. The investigation also reveals a new therapy that shows promise in blocking and killing these tumors.
The research, published in Nature Medicine on July 25, 2024 and led by Dr. Sheila Singh (McMaster University) and Dr. Jason Moffat (Sick Kids, University of Toronto), offers new hope and potential treatments for glioblastoma, the most aggressive form of brain cancer. With existing treatments like surgery, radiation therapy and chemotherapy, the tumors often return, and patient survival is limited to only a few months. With this new treatment, the returning cancer cells were destroyed at least 50 per cent of the time in two of the three diseases tested in preclinical animal models.
Researchers examined models for three different types of cancer including adult glioblastoma, adult lung-to-brain metastasis, and pediatric medulloblastoma. In all three models, treatment led to a doubling of survival time. In two of the three diseases, it led to tumor eradication in at least 50 per cent of the mice.
Research Article Abstract
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood–brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50–100% of mice. Our study identifies a promising multi-targetable PTP4A–ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.