Introduction and Key Funding
Abbie's Army is pleased to announce the finalization of a grant to support a multi-pronged approach for DIPG therapy targeting BDNF-TrkB signalling in the DIPG microenvironment. This $270,000 (£210,000) grant, awarded to the Monje Lab at Stanford University, represents the charity's largest single grant to a US based laboratory.
Principal Investigators
Prof. Michelle Monje: Professor of neuro-oncology and neurological sciences and a paediatric neuro-oncologist at Stanford University School of Medicine.
Research and Clinical Application
The proposed research aims to determine the therapeutic potential of blocking BDNF signalling in DIPG, hypothesizing that this is a key microenvironmental factor fuelling DIPG growth. The majority of the proposal focuses on BDNF as a leading candidate for microenvironmental therapy in DIPG.
The Monje Lab has identified BDNF, a molecule promoting DIPG proliferation, and seeks to block its signalling to inhibit cancer growth. This growth factor is secreted in response to brain activity and plays numerous roles in childhood brain development, including promoting DIPG growth by hijacking developmental mechanisms.
The brain microenvironment has been identified as the chief source of BDNF ligand. Addition of recombinant BDNF protein increases paediatric glioma cell proliferation in patient derived models and activates the canonical downstream MAPK signalling pathway, an effect that is blocked by genetic or pharmacological TrkB inhibition in pHGG.
However, the glioma growth-promoting effects of BDNF in vivo cannot be explained by stimulation of MAPK signalling alone. We therefore examined the effects of BDNF signalling on neuron-to-glioma synapse formation, a newly recognized microenvironmental interaction important for paediatric glioma progression. We find that BDNF-TrkB signalling promotes neuron-to-glioma synaptogenesis in neuron-glioma co-culture. We are presently exploring the role for BDNF-TrkB signaling in glioma synaptic plasticity and function
Challenges of Treating DMG
DIPG hijacks mechanisms of development and plasticity in the childhood brain, making it difficult to treat. Active neurons in the tumour microenvironment robustly promote DIPG growth.
Role of Abbie’s Army in Funding
Abbie's Army carefully reviewed the grant proposal, holding extensive discussions and negotiations with Michelle Monje. The charity's trustees felt there was great potential and reason to be hopeful for the development of an effective combination therapy for DIPG.
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