Poster Presentation NSW State Cancer Conference 2023

Therapeutic value of targeting pro-nerve growth factor and its receptor sortilin in glioblastoma (#133)

Mark Marsland 1 2 , Amiee Dowdell 1 2 , Chen Chen Jiang 1 2 , James Lynam 3 4 , Graig Gedye 2 3 , Phillip Jobling 1 2 , Sam Faulkner 1 2 , Hubert Hondermarck 1 2
  1. University of Newcastle, Callaghan, NSW, Australia
  2. Hunter Medical Research Institute, University of Newcastle, New Lambton Heights NSW 2305, NSW, Australia
  3. Department of Medical Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia
  4. School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia

Background


Glioblastoma (GBM) is the most lethal adult primary brain tumour and over the past decades, treatment strategies for GBM have remained relatively unchanged. Current standard of care consists of maximal safe resection, radiotherapy with concomitant chemotherapy using temozolomide (TMZ) followed by ongoing adjuvant TMZ.  However, the average patient survival after diagnosis is only 15 months. Recent research shows that neurons are underestimated drivers of GBM. Our laboratory has shown that neurons release the neurotrophic factor pro-nerve growth factor (proNGF), while its receptor sortilin is expressed by GBM cells.

Aims


Define the expression and therapeutic value of proNGF and sortilin in GBM.

Methods


A cohort of GBM (n=72) and low-grade glioma (n=20) from the Hunter Cancer Biobank was analysed using immunohistochemistry. ProNGF and sortilin staining intensities were digitally quantified using HALO. Matching plasma samples were analysed by ELISA. We targeted proNGF and sortilin, in vitro and in vivo, using blocking antibodies (anti-proNGF) and pharmacological inhibitors (AF38469). Mouse experiments were performed by the Mark Hughes Foundation (MHF) pipeline.

Results


In clinical samples, proNGF was expressed in neurons while sortilin was present in both neurons and GBM cells, suggesting that proNGF released by neurons may stimulate GBM tumours through the activation of sortilin signalling. GBM was associated with increased sortilin (p=0.0029). High sortilin levels were associated with lower patient survival (p=0.0268). Western blots also revealed higher sortilin in GBM cells. Blocking sortilin inhibited cancer cell migration, while not affecting viability, which demonstrated that sortilin may drive GBM progression. However, when used in combination, blocking sortilin enhanced the effects of TMZ in some GBM cell lines. In the mouse, blocking proNGF reduced tumour size with a small increase in survival.

Conclusion


This study reveals the overexpression of proNGF and sortilin in GBM as a driving force for tumour aggressiveness that could be targeted to treat GBM and increase the efficacy of current treatments.

Consumer engagement


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