Abstract 4755: Extracellular GRP78 inhibition reverses drug and immune resistance in cancer cells

Abstract

Abstract CBT300 was created from Creative BioTherapeutics’ discovery that drug resistant recurrent cancer cells up-regulate a survival pathway that results in the expression of extracellular Glucose-Regulated Protein 78 (ecGRP78) in the tumor microenvironment (TME). This TME ecGRP78 binds to cancer and immune cell surfaces, which induces a cascade of events to increase drug resistance, immune suppression, and cancer stem cell (CSC) formation. CBT300 targets surface bound ecGRP78 that has been found on breast, lung, ovarian, prostate, melanoma, multiple myeloma, colon, pediatric and adult brain tumors. We can now show that inhibition of ecGRP78 can a) induce apoptosis of drug resistant tumor cells, b) eliminate drug and immune resistance showing synergistic effects with chemotherapy and immunotherapy, c) decrease the amount of chemotherapy about 90% in combination with CBT300. Recent publications show that ecGRP78 is found on many types of tumor cell surfaces but not on normal cell surfaces. In fact, cell surface bound ecGRP78 is important for many aspects of cancer development, including cell survival, proliferation, chemoresistance, angiogenesis, metastasis formation, immune suppression, and stem cell formation. Recently, it has been shown that increased ecGRP78 expression in metastatic breast cancer, glioblastoma and multiple myeloma patients was significantly associated with later stage, increased distant metastasis, increased aggressiveness, shorter disease-free survival, and decreased overall survival. In studies to help understand how ecGRP78 causes tumor progression and drug and immune resistance, we discovered a novel ecGRP78 binding transmembrane protein on TNBC, and brain cancer cells called Receptor Tyrosine Kinase Orphan Receptor-1 (ROR1). Using the GRP78 binding domain from ROR1 and a human Fc domain, we created a biologic fusion protein that is a potent and specific ecGRP78 inhibitor called CBT300. We now show that CBT300’s elimination of csGRP78 destabilizes and removes oncofetal proteins ROR1, and Cripto, and checkpoint protein PD-L1 from tumor cell surfaces resulting in reversal of chemoresistance, reduction in immune suppression, inhibition of stem cell phenotype and increased tumor cell apoptosis. Our results with CBT300 demonstrate proof of concept data in vitro and in vivo for our novel ecGRP78 inhibitor on several drug resistant cancers demonstrating the potential to provide a major advance in the treatment of drug resistant cancers either alone or in combination with lower doses of chemotherapy. Exploiting a novel mechanism of action with a non-toxic, efficacious and cost effective biologic therapy that has shown increased survival in recurrent cancers will bring new hope for these patients. Citation Format: Donald J. Davidson, Jorryn Zelek, Elizabeth Stolarik, Mariah Thigpen, Anita Davidson, DPT. Extracellular GRP78 inhibition reverses drug and immune resistance in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4755.