Project Summary:
Gliomas are the most prevalent brain tumours and predominantly arise from glial cells. The World Health Organization (WHO) grades gliomas on a scale of I to IV, reflecting their degree of malignancy. The higher the grade the more severe the tumour in terms of growth and invasion. Grade I tumours are benign and can be cured while grade IV gliomas (also called Glioblastoma or GBM) are very aggressive forms of brain cancer.
Patients with GBM are among the most disadvantaged cancer patients in the healthcare system. The overall survival outcome for GBM is dismal with a median survival of 15 months. Standard GBM management typically involves surgical resection followed by radiotherapy and adjuvant chemotherapy with temozolomide (TMZ), but relapses usually occur within a month after initiating treatments.
The difficulty in effectively treating GBM patients is largely due to a fast-growing malignancy, providing several hindrances to understanding the molecular mechanisms underpinning disease progression and thereby constraining suitable therapeutic development. We have identified a unique requirement for lipid metabolism to support GBM malignancy and show in preclinical models that blocking lipid metabolism slows GBM growth. In this study, we will uncover novel proteins that are requisite for aberrant lipid metabolism and that confer a survival advantage in glioblastoma. Outcomes of this work range from elucidating in-depth mechanisms of tumorigenesis to conducting preclinical translational research. This will provide a rich resource to guide the genesis of a new class of metabolic-based drug for clinical treatment of glioblastoma patients.
Outcomes:
Alterations of metabolic activities support the malignant properties of cancer cells; however, the role of lipid metabolism in primary brain cancer biology has received relatively little attention. We have now generated a genetic model of glioblastoma to understand how specific alterations in lipid accumulation can lead to the pathogenesis of this disease. Our finding demonstrates that glioblastoma cells utilize differences in metabolic processes driven from fats (called lipids) allowing tumour cells to advantageously grow at greater rates to normal brain cells.
Secondly, we investigated the relationship between hypoxia and lipid metabolism in glioblastoma. Hypoxia develops very early during tumour establishment due to an inadequate blood supply around the tumour. Hypoxia is regarded as a major determinant of tumour aggressiveness because it induces remodelling of the metabolic landscape, promotes progression and causes therapeutic resistance. Our results suggest that products of lipid breakdown are an important fuel source required to meet the biosynthetic and bioenergetic demands of malignant growth during hypoxia. This represents an important conceptual advance, as currently there is scarce understanding of the pathways that sustain the high metabolic demands imposed on glioblastoma cells during hypoxia.
Importantly, we have also identified two agents that are capable of inhibiting these lipids driven metabolic processes. We therefore aim to test these agents to determine whether they can inhibit glioblastoma progression in animal model. Overall, our data shows that glioblastoma cells have unique lipid metabolic dependence that can be exploited for therapeutic gain.
We are thankful for seed grant funding from the Brain Foundation.
Outcomes submitted July 2021.
The Brain Foundation is dedicated to funding the next generation of Australian research into brain disorders, diseases, and injuries, with the ultimate goal of advancing diagnoses, treatments, and patient outcomes.