Poster Presentation NSW State Cancer Conference 2023

Therapeutic potential of the neurotrophin receptor p75NTR in glioblastoma multiforme (#112)

Amiee AD Dowdell 1 2 , Mark MM Marsland 1 2 , Sam SF Faulkner 1 2 , Craig CG Gedye 1 3 , James JL Lynam 1 3 4 , Cassandra CG Griffin 1 3 5 , Chen Chen CCJ Jiang 1 2 , Hubert HH Hondermarck 1 2
  1. Hunter Medical Research Institute, , University of Newcastle, New Lambton Heights, NSW, Australia
  2. Cancer Neuroscience Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
  3. School of Medicine and Public Health, College of Health, Medicine and Wellbeing,, University of Newcastle, Callaghan, NSW, Australia
  4. Department of Medical Oncology, Calvary Mater, Newcastle, NSW, Australia
  5. Hunter Cancer Biobank, Mark Hughes Foundation Regional Biospecimen and Research Services, University of Newcastle, Callaghan, NSW, Australia

Introduction: Glioblastoma multiforme (GBM) is a devastating, lethal brain cancer. Temozolomide (TMZ) is the main chemotherapeutic drug used in the treatment of GBM, but unfortunately its efficacy is limited, and patient survival has remained dismal. Our laboratory’s interest is in the role of neurotrophic factors and their receptors, such as p75 neurotrophin receptors (p75NTR), in cancers. P75NTR is part of the neurotrophin binding family of receptors involved in neuronal cell differentiation, survival, and death and has been shown to be involved in other malignancies. In this study, we hypothesised p75NTR is overexpressed and a therapeutic target in GBM.

Objective: Define the expression of p75NTR and its therapeutic value in GBM.

Methods and Results: A cohort of GBM (n=70) and low-grade glioma (LGG) (n=20) from the Hunter Cancer Biobank was analysed using immunohistochemistry for p75NTR and quantified using the HALO software. Western blotting was utilised to evaluate the expression of p75NTR in a panel of patient-derived GBM cell lines, which were also used to test the impact of targeting p75NTR on cell survival and colony formation. The IHC results show that p75NTR was expressed at higher levels in GBM compared to LGG (P = 0.0009). Our in vitro data reveals that GBM cells overexpressed p75NTR protein compared to normal astrocytes. Targeting p75NTR in vitro with pharmacological inhibitors, we found that the inhibition of p75NTR potentiated the efficacy of TMZ, including in TMZ resistant cell lines.

Conclusion: P75NTR is overexpressed in GBM and can be targeted to increase the efficacy of chemotherapy. This warrants further investigation in animal models.

Consumer engagement: This project was funded by the MHF who represent the brain cancer community. Kathryn Leaney, from the Cancer Voices NSW, was the consumer representative.