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Aberrant Signaling and Metabolism in Malignant Brain Tumours

Ab Guha
Ab Guha, winner of the
Lister Prize

Joseph Lister worked patiently on controlling the development of osteomyelitis in open fractures through application of the scientific method. He knew Pasteur's method of using heat to kill bacteria would not be safe, so he experimented with antiseptics. The Lister Prize is awarded to a senior investigator in our department who has shown outstanding and continuing productivity of international stature. Ab Guha has been working patiently to understand the molecular basis of malignant brain tumors, with the hope this knowledge will lead to novel therapies. Here's how Ab told the story at a recent University Rounds. After thanking his family, mentors, colleagues and lab members, Ab praised the Surgeon Scientist Program and the culture of academic excellence in surgery he experienced during his training and later as he mentors the next generation of surgeon-scientists.

Ab's research has focused on the molecular basis of primary malignant brain tumours, the most common of which is the Glioblastoma Multiforme (GBM). GBMs occur in ~12/100,000 people. Despite treatment by surgery, radiation and chemotherapy, the median survival remains 12-16 months. There are two or more ways that a GBM can arise. Though pathologically indistinguishable, they harbour molecular differences including overexpressed and/or mutated growth factor receptors and intracellular signaling pathways. Ab's research has focused on two of these aberrant receptors (PDGFR- Platelet Derived Growth Factor Receptor; EGFR- Epidermal Growth Factor Receptor), which have been shown to be overexpressed and activated, leading to increased tumorgenic signals. Biological

therapies, based on pre-clinical work by Ab and others, has led to clinical trials with drugs that inhibit these receptors. Since GBMs are not driven by a single genetic alteration, Ab predicted targeting one receptor or pathway will likely not succeed, and will require therapies against multiple targets.

Ab's work has demonstrated activation of Ras, a key intracellular signaling pathway from these receptors, which carries tumorigenic signals to the cell's nucleus. Therapies inhibiting this pathway are under clinical trials. Ab's lab has developed transgenic mouse brain tumour models, based on the molecular alterations found in human GBMs. These models have been used to examine interactions between these molecular alterations to determine which are driving the tumour growth and which are bystander alterations, which ones initiate the tumour vs. which ones makes them progress. In addition to testing the relevance of the known molecular alterations, these mouse models, can also be used to discover new genetic alterations in human tumours. Ab stressed the point about the critical node that surgeon-scientists hold in tumour banking and facilitating their own research, and the work of other basic scientists who do not have ready access to these precious clinical materials.

Ab described how tumours utilize glucose for energy vs. normal cells. In tumours such as GBMs, energy is derived from glycolysis outside the mitochondria. Although less efficient in making ATP this form of glucose utilization allows the tumour cells to survive and accumulate building blocks of further growth, including lipids, aminoacids and nucleic acids. Ab's group has demonstrated the enzyme Hexosekinase2 to be an important mediator of abnormal glucose metabolism in human GBMs. Pharmaceutical companies are increasingly interested in targeting these aberrant metabolic pathways in tumours as potential anti-cancer agents.

Ab wrapped up his talk with a forward look at the field of neuro-oncology to which he and his colleagues have made significant contributions.

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