Table 2.
General characteristics of GRP78-based treatments.
| Treatment | Type | Target | Enhances effects of: | Combination therapy in GBM | Mechanism | Effect | Model | Clinical trials | References |
|---|---|---|---|---|---|---|---|---|---|
| Epigallocatechin 3-gallate (EGCG) | Natural product | GRP78 (NBD domain) | TMZ; Others: 5-fluorouracil taxol vinblastine gemcitabine and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), doxorubicin, paclitaxel, interferon-α2b |
TMZ + EGCG | Impairs GRP78 function | Enhanced cytotoxicity when used with TMZ (not as monotherapy) | Human cell lines, in vivo | No | (58, 65) |
| Honokiol | Natural product | GRP78 (NBD domain) | TMZ; Others: fenretinide, bortezomib |
TMZ + honokiol | Interferes with GRP78 folding | Induced ER stress-mediated apoptosis +/− TMZ | Human cell lines | No | (66–68) |
| OSU-03012 | Celecoxib derivative | GRP78 (NBD domain) | Radiotherapy | Radiotherapy + OSU-03012; GRP78 inhibition further enhances effects | PDK1 inhibitor, GRP78 inhibitor, PERK signaling | Enhanced radiosensitivity, prolonged survival | Human cell lines, in vivo mouse models | No | (65, 69) |
| Celecoxib and bortemozib | Celecoxib-based | ER stress | N/A | Celecoxib + bortezomib + GRP78 inhibition | Augment ER stress | Induced ER stress-mediated apoptosis | Human cell lines | No | (70) |
| Perillyl alcohol (NEO100) | Monoterpene | ER stress | TMZ; Others: DMC, nelfinavir |
TMZ + NEO100 | Disruption of survival pathways | Induced more apoptosis +/− TMZ, reduced GBM invasive capacity, prolonged survival | Human cell lines, in vivo | Yes | (71–73) |
| HA15 | Small molecule inhibitor | GRP78 | N/A | N/A | Binds and inhibits GRP78 and disrupts GRP78 complexes with UPR transmembrane stress sensors | Induction of apoptosis | Human cell lines, in vivo mouse models | No | (74, 75) |
| IT-139 | Small molecule inhibitor | GRP78 | Chemotherapy | N/A - not yet studied in GBM | Involves transcriptional and post-transcriptional mechanisms | Decreases therapeutic resistance | Human cell lines, in vivo human xenograft studies | No | (76) |
| EGF-SubA | Fusion protein | GRP78 | TMZ and ionizing radiation | TMZ + radiation therapy + EGF-SubA | Cleaves GRP78 | Delayed tumor growth, enhanced effects of TMZ and ionizing radiation | Human cell lines, in vivo mouse models | No | (77) |
| Anti-GRP78 antibody | Antibody-based | surface GRP78 | Ionizing radiation | ionizing radiation + anti-GRP78 antibody | Suppression of PI3K/Akt/mTOR signaling | Enhanced effects of ionizing radiation, resulted in tumor delay | Human cell lines, in vivo mouse xenograft models | No | (45) |
| RGD ligand-directed phage with GRP78 promoter | Treatment delivery | GRP78 | Expression of therapeutic transgenes | N/A | RGD tumor homing ligand and GRP78 promoter | Improved expression of therapeutic transgenes compared to standard promotor phage | Human cell lines, in vivo | No | (78) |
| TMZ-induced AAV phage with GRP78 promoter | Treatment delivery | GRP78 | TMZ, expression of therapeutic transgenes | TMZ + phage | RGD4C ligand binding, TMZ-induced GRP78 expression activates therapeutic genes with GRP78 promoter | Permits dose reductions of TMZ | Human cell lines, mouse xenograft models | No | (79) |
| GRP78-binding peptide (GIRLPG) | Treatment delivery | GRP78 | Radiation therapy, expression of therapeutic transgenes | Radiation + phage | GIRLPG peptide binds GRP78 and allows for adenovirus-mediated gene delivery to target tumor cells responding to radiation therapy | Enhances radiation therapy and therapeutic gene expression | Human cell lines, mouse xenograft models | No | (80) |