Building the case for the calcitonin receptor as a viable target for the treatment of glioblastoma

Abstract

Researchers are actively seeking novel targeted therapies for the brain tumour glioblastoma (GBM) as the mean survival is less than 15 months. Here we discuss the proposal that the calcitonin receptor (CT Receptor), expressed in 76–86% of patient biopsies, is expressed by both malignant glioma cells and putative glioma stem cells (GSCs), and therefore represents a potential therapeutic target. Forty-two per cent (42%) of high-grade glioma (HGG; representative of GSCs) cell lines express CT Receptor protein. CT Receptors are widely expressed throughout the life cycle of organisms and in some instances promote apoptosis. Which of the common isoforms of the CT Receptor are predominantly expressed is currently unknown, but a functional response to cell stress of the insert-positive isoform is hypothesised. A model for resistant malignancies is one in which chemotherapy plays a direct role in activating quiescent stem cells for replacement of the tumour tissue hierarchy. The putative role that the CT Receptor plays in maintenance of quiescent cancer stem cells is discussed in view of the activation of the Notch–CT Receptor–collagen V axis in quiescent muscle (satellite) stem cells. The pharmacological CT response profiles of four of the HGG cell lines were reported. Both CT responders and non-responders were sensitive to an immunotoxin based on an anti-CT Receptor antibody. The CALCR mRNA exhibits alternative splicing commonly associated with cancer cells, which could result in the atypical pharmacology exhibited by CT non-responders and an explanation of tumour suppression. Due to the inherent instability of CALCR mRNA, analysis of CT Receptor protein in patient samples will lead to improved data for the expression of CT Receptor in GBM and other cancers, and an understanding of the role and activity of the splice variants. This knowledge will aid the effective targeting of this receptor for treatment of GBM.

Alternative RNA Splicing—The Trojan Horse of Cancer Cells in Chemotherapy

“…As possible reasons for inactivation were AS splicing, a switch to the CT Receptor b isoform or other mutations [ 159 ]. It was concluded that targeting the CT Receptor by immunotoxin is expected to provide an additional “knife”, in combination with traditional therapy of GBM [ 160 ]. The Glycogen Synthase Kinase-3 gene (GSK3) is responsible for a regulatory Ser/Thr protein kinase that exists in two distinct isoforms, GSK3α and GSK3β [ 161 ].…”

Strategic Development of an Immunotoxin for the Treatment of Glioblastoma and Other Tumours Expressing the Calcitonin Receptor

“…The tumour hierarchy or architecture includes regions of necrosis and oedema [ 5 ], where the blood–brain barrier is compromised and antibodies are able to penetrate [ 6 ] pro-inflammatory micro-environments with cellular infiltrates and vascular-like structures (vascular mimicry [ 7 ]) with proliferative domains, which are located primarily towards the tumour periphery. Within these latter hyperplastic structures, pericyte precursors and endothelial cells share the same genetic modifications as glioma stem-like cells (GSC), supporting plasticity with regard to differentiation lineages and the existence of dominant GSC clones [ 8 ].…”

“…CT Receptors are widely expressed through the lifecycle of organisms, in several physiological conditions and diseases, including several cancers such as GBM and prostate cancer [ 5 , 36 ]. At least two different isoforms (insert-negative CT a Receptor and insert-positive CT b Receptor) have been identified in mammals.…”

“…The latter isoform appears to be expressed across mammalian species, except Muroidea, and has an extra 16–18 amino acid-insert at the beginning of the second transmembrane span. The relative pharmacology of these isoforms has been summarised [ 5 ] and discussed in detail [ 37 , 38 , 39 ]. CT Receptors are encoded by the CALCR gene, which has been mapped to human chromosome 7 q21.3.…”

“…In view of the negative CT pharmacological profile, it is unlikely that CT analogues would prove useful for treating CT Receptor-positive GBM [ 44 ]. The negative profile raises the possibility that the CT Receptor is mutated in these HGG lines (PK1, JK2, and WK1), which would suggest a role for the CT Receptor as a tumour suppressor or that there is predominant gene expression of the insert-positive CT b Receptor isoform [ 5 ] with a potential role as an oncogene.…”