Amiee Dowdell has started her PhD in February 2021 on a project entitled “Targeting the nerve-cancer cell crosstalk in glioblastoma”, supervised by Professor Hubert Hondermarck.
Glioblastoma (GBM) is a devastating cancer with currently no effective treatment. To date, therapeutic strategies have all been directed towards targeting cancer cells, but unfortunately patient survival rates have remained stagnant and therefore, the GBM field is in need of new thinking. Recent evidence in other cancers, including from our laboratory, have demonstrated the crucial role played by neurons in tumourigenesis. Neurons secrete neurotransmitters and neurotrophic growth factors that fuel cancer cell proliferation and invasion.
We think that these recent discoveries provide an explanation as to why GBMs are so aggressive: they develop in a neuronal microenvironment where the stimulatory impact of neurons is maximal.
The objective of this project is to treat GBM by disrupting the crosstalk between GBM cells and neurons. We have obtained exciting preliminary data showing that pro-nerve growth factor (proNGF), known to stimulate neurogenesis, and its receptors p75NTR and sortilin, are overexpressed and released by GBM cells and can be targeted to inhibit GBM cell growth and survival. The objective of the present project is to target proNGF and its receptors to disrupt the neuron-cancer cell crosstalk and inhibit the stimulatory impact of neurons in GBM.
The first aim is to analyse the overexpression of proNGF and its receptors in a large cohorts of glioblastoma patient samples. ProNGF and its receptors will be assayed by immunohistochemistry in tissue samples and by ELISA in blood samples. The second aim is to target proNGF and its receptors using blocking antibodies that have been developed in collaboration with our partner in industry Biosensis Pty Ltd (Adelaide). The therapeutic activity of blocking antibodies against proNGF, p75NTR and sortilin will be tested in vitro and in vivo, using a mouse model of GBM. Together, we hope to deliver an innovative new treatment for GBM based on targeting the neuron-cancer cell crosstalk.
Significant progress has been made during the last 6 months.
We have demonstrated the following points
- Endoplasmic reticulum stress (ER stress) is associated with progression of glioblastoma (GBM).
- The ER stress-activated transcription factor XBP1 stimulates GBM cell survival, and importantly, targeting XBP1 with pharmacological inhibitors induces GBM cell death. Therefore XBP1 is a new potential therapeutic target in GBM.
- We now start in vivo experiments to pre-clinically validate the therapeutic value of targeting XBP1 in GBM.
2- The data are going to be presented at the next Australian Brain Cancer Research Alliance conference in Brisbane (16-18 October 2022):
- Amiee Dowdell, Mark Marsland, Mark Baker, Sam Faulkner, Craig Gedye, Chen Chen Jiang, Hubert Hondermarck. Targeting the pro-survival transcription factor XBP1 sensitises glioblastoma to treatment
3- Two publications on the under preparation:
- Mark Marsland, Amiee Dowdell, Sam Faulkner, Phil Jobling, Craig Gedye, Mark Baker, Chen Chen Jiang, Hubert Hondermarck.. ProNGF expression and targeting in glioblastoma multiform. Will be submitted to International Journal of Molecular Sciences.
- Amiee Dowdell, Mark Marsland, Sam Faulkner, Chen Chen Jiang and Hubert Hondermarck. The membrane protein sortilin is a biomarker and potential target in glioblastoma. Will be submitted to Cancers.
Thank you
We sincerely thank the donors for their donation. Clearly this project would not have been possible without them and we do as much as we can to be successful in providing an efficient cure for brain cancer
Amiee and Hubert