Inhibition of cell surface GRP78 on brain tumors reverses drug resistance and stops cancer stem cell expansion.

Even with the best available treatments for patients with brain cancer, the recurrence rates are nearly 100%. A major cause of recurrence is the expansion of brain tumor stem cells. These stem cells are highly resistant to chemotherapy and radiation and have strong immunosuppressive characteristics. Surface-bound glucose-regulated protein 78 (GRP78) is a survival factor that is essential for tumor stem cell expansion. Cell surface GRP78, compared to endoplasmic reticulum-resident GRP78, has been defined as a stress-induced factor that can cause aggressive growth, chemoresistance, radioresistance, and stem cell expansion in brain tumors. Here, we focused on how cell surface GRP78 induces these protumor effects and how these effects can be reversed. Herein, our data show that surface GRP78 binds and stabilizes a novel transmembrane tyrosine kinase called receptor tyrosine kinase-like orphan receptor-1, an oncofetal factor called Cripto, and a checkpoint protein called programed death-ligand 1 in brain tumor cells. To specifically inhibit only cell surface GRP78, we created and tested several GRP78 inhibitors, CBT100, CBT200, and CBT300. We found that these GRP78 inhibitors regressed pediatric and adult brain tumor neurospheres and eliminated receptor tyrosine kinase-like orphan receptor-1, Cripto, and programed death-ligand 1 expression, leading to tumor cell apoptosis. Cell surface GRP78 inhibition with systemic dosing of GRP78 inhibitors, in preclinical orthotopic brain tumor mouse models, demonstrated significant increases in overall survival and durable regressions in 40 to 70% of treated mice compared to control mice.