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Abstract
Glioblastoma (GBM) is the most common primary brain tumor, carrying a very poor prognosis, with median overall survival at about 12 to 15 months despite surgical resection, chemotherapy with temozolomide (TMZ), and radiation therapy. GBM recurs in the vast majority of patients, with recurrent tumors commonly displaying increase in resistance to standard of care chemotherapy, TMZ, as well as radiotherapy. One of the most commonly cited mechanisms of chemotherapeutic and radio-resistance occurs via the glucose-regulated protein 78 (GRP78), a well-studied mediator of the unfolded protein response (UPR), that has also demonstrated potential as a biomarker in GBM. Overexpression of GRP78 has been directly correlated with malignant tumor characteristics, including higher tumor grade, cellular proliferation, migration, invasion, poorer responses to TMZ and radiation therapy, and poorer patient outcomes. GRP78 expression is also higher in GBM tumor cells upon recurrence. Meanwhile, knockdown or suppression of GRP78 has been shown to sensitize cells to TMZ and radiation therapy. In light of these findings, various novel developing therapies are targeting GRP78 as monotherapies, combination therapies that enhance the effects of TMZ and radiation therapy, and as treatment delivery modalities. In this review, we delineate the mechanisms by which GRP78 has been noted to specifically modulate glioblastoma behavior and discuss current developing therapies involving GRP78 in GBM. While further research is necessary to translate these developing therapies into clinical settings, GRP78-based therapies hold promise in improving current standard-of-care GBM therapy and may ultimately lead to improved patient outcomes.
Highlights
Gliomas: BackgroundGliomas are the most commonly diagnosed primary neoplasms in the central nervous system, constituting up to 81% of malignant brain tumors [1]
We aim to summarize the literature assessing the role of glucose-regulated protein 78 (GRP78) and other mediators of the unfolded protein response (UPR) within GBM, including novel studies exploring the role of the UPR in glioma stem cells
The [3] protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway has been shown to initiate signaling that promotes protective metabolic processes such as glycolysis under cell stress [52], while mediating autophagy responses to targeted GRP78 therapies such as OSU-03012, a treatment discussed in detail below [53]
Summary
Gliomas: BackgroundGliomas are the most commonly diagnosed primary neoplasms in the central nervous system, constituting up to 81% of malignant brain tumors [1]. The [3] PERK pathway has been shown to initiate signaling that promotes protective metabolic processes such as glycolysis under cell stress [52], while mediating autophagy responses to targeted GRP78 therapies such as OSU-03012, a treatment discussed in detail below [53].
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