Poster Presentation 35th Lorne Cancer Conference 2023

The expression activity and targeting of calcitonin receptor a putative tumour suppressor in the brain tumour glioblastoma (#355)

Pragya Gupta 1 , Tina C Lavranos 2 , David L Hare 1 , Peter J Wookey 1 2
  1. Department of Medicine-Austin, University of Melbourne, Heidelberg, VIC, Australia
  2. Apop Biosciences, North Melbourne, Victoria, Australia

Calcitonin receptor (CT Receptor) is highly expressed (76-86%) in the brain tumour glioblastoma by glioma cells and glioma stem cells [GSCs] (1-2). The current consensus is that GSCs are highly invasive and as quiescent GSCs, provide resistance to conventional therapeutics. For this reason we investigated CT Receptor as a potential therapeutic target using high grade glioma (HGG) cell lines that represent GSCs. Pharmacological data from 4 HGG cell lines that express CT Receptor show that 3 lines (JK2, PB1 & WK1) do not respond to the agonist calcitonin in contrast to SB2b, in which adenylyl cyclase is partially activated. Evidence that CT Receptor acts as a tumour suppressor in glioblastoma and other tumours (1) is supported by inactivation. A monoclonal antibody (CalRexinTM: www.apopbiosciences.com) was developed that binds an epitope in the extracellular domain, is accumulated by live cells and acts as a targeting vector. CT Receptor was detected on immunoblots of membrane fractions from the HGG cell lines except the PB1. Immunotoxins (CalRexinTM:dianthin and CalRexinTM:gelonin) and an antibody:drug conjugate (ADC, CalRexinTM:monomethyl auristatin E) were synthesised and tested in HGG cell lines (3). When tested on JK2, SB2b and WK1, both immunotoxins were 250 times more potent than the ADC in the presence of the triterpene glycoside SO1861 that enhances endo-lysosomal escape (3). PB1, which expresses only low levels of CT Receptor, was resistant to the immunotoxins. Regardless of its pharmacological status, CT Receptor is useful for targeting glioblastoma and other cancers.

 

  1. Gupta P, et al. Building the case for the calcitonin receptor as a viable target for the treatment of glioblastoma. Therap Adv Med Oncol, 12:1-15, 2020.
  2. Gupta P, Hare DL, Wookey PJ. Strategic development of an immunotoxin for the treatment of glioblastoma and other tumours expressing the calcitonin receptor. Cells 10:2347, 2021.
  3. Gilabert-Oriol R, et al. Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high grade glioma cell lines derived from glioblastoma. Cancer Immunol Immunother 66:1217-1228, 2017.