Glioblastoma cancer stem cells: Biomarker and therapeutic advances

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. It accounts for fifty-two percent of primary brain malignancies in the United States and twenty percent of all primary intracranial tumors. Despite the current standard therapies of maximal safe surgical resection followed by temozolomide and radiotherapy, the median patient survival is still less than 2 years due to inevitable tumor recurrence. Glioblastoma cancer stem cells (GSCs) are a subgroup of tumor cells that are radiation and chemotherapy resistant and likely contribute to rapid tumor recurrence. In order to gain a better understanding of the many GBM-associated mutations, analysis of the GBM cancer genome is on-going; however, innovative strategies to target GSCs and overcome tumor resistance are needed to improve patient survival. Cancer stem cell biology studies reveal basic understandings of GSC resistance patterns and therapeutic responses. Membrane proteomics using phage and yeast display libraries provides a method to identify novel antibodies and surface antigens to better recognize, isolate, and target GSCs. Altogether, basic GBM and GSC genetics and proteomics studies combined with strategies to discover GSC-targeting agents could lead to novel treatments that significantly improve patient survival and quality of life.

Keywords: Biomarkers; Cancer stem cells; Glioblastoma; Phage antibody display; Yeast antibody display.

Figure 1

GSC surface protein marker enrichment using a yeast display library. Enrichment for GSC-specific scFvs is accomplished by multiple positive selection rounds with yeast expressing scFv. GSC-bound scFvs are validated for GSC specificity by differential cell binding against GSCs, non-GSCs, and normal neural cells, followed by evaluation for scFv ability to discriminate tumor initiating and non-tumorigenic GBM cells. Adapted from Ebben et al.(108) and Wang et al.(77).

Figure 2

Targeting glioblastoma cancer stem cells is necessary to prevent tumor recurrence. GBM cancer stem cells are resistant to the current standard of care: surgical resection, radiotherapy and temozolomide. Therapeutic approaches and strategies to target GSCs in addition to the differentiated tumor cells are necessary to effectively treat the entire cancer and prevent tumor recurrence.