Abstract
New strategies aimed at treatment of glioblastoma are frequently proposed to overcome poor prognosis. Recently, research has focused on glioma stem cells (GSCs), some quiescent, which drive expansion of glioblastoma and provide the complexity and heterogeneity of the tumour hierarchy. Targeting quiescent GSCs is beyond the capability of conventional drugs such as temozolomide. 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 GSCs. Forty-two percent (42%) of high-grade glioma (HGG; representative of GSCs) cell lines available from one source express CT Receptor protein in cell culture. The pharmacological calcitonin (CT)-response profiles of four of the HGG cell lines were reported, suggesting mutational/splicing inactivation. Alternative splicing, commonly associated with cancer cells, could result in the predominant expression of the insert-positive isoform and explain the atypical pharmacology exhibited by CT non-responders. A role for the CT Receptor as a putative tumour suppressor and/or oncoprotein is discussed. Both CT responders and non-responders were sensitive to immunotoxins based on an anti-CT Receptor antibody conjugated to ribosomal-inactivating proteins. Sensitivity was increased by several logs with the triterpene glycoside SO1861, an endosomal escape enhancer. Under these conditions, the immunotoxins were 250–300 times more potent than an equivalent antibody conjugated with monomethyl auristatin E. Further refinements for improving the penetration of solid tumours are discussed. With this knowledge, a potential strategy for effective targeting of CSCs expressing this receptor is proposed for the treatment of GBM.
Highlights
These results indicate that even with pharmacological inactivation of the CT Receptor, the immunotoxin is a potent reagent to promote cell death of high-grade glioma (HGG) cell lines
Patients diagnosed with glioblastoma have a poor prognosis and quality of life
The CT Receptor is found expressed by a high proportion of patient biopsies and is expressed by malignant glioma cells and putative glioma stem cells
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Brain tumour-initiating cells were enriched in experiments using the marker CD133 [18,19], and CD133+ /CT Receptor+ cells were identified in GBM biopsies from patients [20]. Rare quiescent sox2(+) cells, which are enriched following anti-mitotic treatment (temozolomide, TMZ), drive tumour regrowth in a similar mouse model of medulloblastoma [23]. In this context, conventional treatments of GBM following cyto-reductive surgery, namely, radiotherapy and chemotherapy, which target proliferating cells, will likely have a low probability of success. A platelet-derived growth factor (PDGF)-driven glioma subpopulation of tumour cells has been characterised as a stem-like population with the preference for the perivascular niche [24], which perhaps suggests their identity as pericyte precursors. Further discussion about the identity of brain tumour stem cells has been reviewed recently [30]
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