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Microglia targeting of Glioblastoma Multiforme (GBM)

 Lead PI: Prof. Manuel Graeber

 

Research Idea

We plan to develop and refine technology to allow us to send genetically-enhanced microglia into diseased brains to directly target glioblastoma multiforme cells. 

Problem

Our research is focused on a novel strategy that makes use of the presence of microglia within diffuse glioma. Microglia are the resident defence cells of the central nervous system. They play a maintenance role in the healthy brain and an immunological role in the diseased brain. Within a glioma, microglia make up the largest population of tumour-infiltrating cells, contributing at least one third of the total tumour mass. Previous work has shown that high-grade gliomas attract microglia and subsequently control microglial activity to support tumour growth and angiogenesis (blood vessel growth). We are interested in whether this ‘fatal attraction’ can be used against the tumor. We plan to use transplantation of bone-marrow-derived genetically enhanced microglia precursors to track down and target infiltrating glioma cells. 

Solution 

Our approach is characterised by a unique combination of factors including Professor Graeber’s research interests and his position at the Brain and Mind Research Institute (BMRI) which bridges neuroscience and oncology. Prof. Graeber is an international authority in the field of microglia, has a strong background in neuroscience and neurogenetics, and is clinically trained as a surgical neuropathologist. As the chair of a university department of neuropathology and subsequently head of a division of neuropathology for almost a decade, Prof. Graeber signed out many glioblastoma multiforme diagnoses:

“I felt like I was merely issuing death sentences, because there is no cure, so I decided to try and do something about the cause. This is why I moved to the BMRI, which offered a unique position to allow us to develop a new treatment for diffuse glioma.” 

- Professor Manuel Graeber

Why now? 

We believe the required technologies are now at hand, in particular, transcription activator-like effector nucleases (TALENs). TALENs provide the capability to easily alter genes to yield potential therapeutic strategies for genetic diseases. We have established collaboration with Professor Richard Banati at the Australian Nuclear Science and Technology Organisation (ANSTO). Prof. Banati has pioneered a method to image the activation of microglia in vivo, and his team has recently developed new probes for microglia. These factors and facilities at the BMRI provide a feasible route to clinical translation. 

Approach

We have established a syngeneic rat glioblastoma model (a genetically-identical rat population used in tumour research). The glioblastoma model will determine the contribution of bone marrow-derived microglia to the population of tumour-associated macrophages (activated microglia). Our data indicate that a significant number of microglia in gliomas are originally blood-derived – they were recruited to the tumour from outside the CNS. This means there is a potentially powerful new route of access to the brain we can use in our novel GBM treatment approach. 

Impact 

We believe our planned research program is a significant and fundamental approach to diffuse glioma treatment and differs from those ever undertaken. We need a glioma treatment that is as effective as an antibiotic for an infection or aspirin against fever or headache. 

Team & Partners 

  • Professor Manuel Graeber, Barnet-Cropper Chair of Brain Tumor Research, Brain & Mind Research Institute (BMRI), University of Sydney
  • Professor Richard Banati (ANSTO) 
  • Dr Damian Holsinger, Laboratory of Molecular Neuroscience, BMRI, and Lecturer in Neuroscience, University of Sydney. 

 

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