Abstract A060: GRP78 and cytokine inhibition displays complete regression of ovarian tumors in mice

Abstract There are no therapies to permanently eliminate ovarian cancer metastasis and drug-resistant recurrences associated with late-stage disease. Since early ovarian cancer is asymptomatic, about 70% of cases are detected in late-stage with existing metastasis. Despite standard-of-care therapy of optimal cytoreductive surgery and adjuvant chemotherapy, nearly 80% of patients will develop recurrent treatment resistance resulting in a 5-year survival rate below 30%. The 2024 World Ovarian Cancer Coalition Briefing predicted a worldwide ovarian cancer escalation of 55% from 324,603 (2022) to almost 500,000 women by 2050 with mortality surging to nearly 70% by 2050. The Coalition urges the global health community to prioritize Ovarian cancer in global health, integrate Ovarian cancer into global women’s health initiatives and address health inequities ensuring access to treatment is universal. Consequently, it is imperative new targets, and novel therapies are developed to reverse therapy resistance of Ovarian cancer to improve patient survival. Creative BioTherapeutics has discovered that in the tumor microenvironment of quiescent and recurrent drug-resistant cancers several survival pathways are up regulated. The upregulation of these pathways result in the secretion of extracellular Glucose-Regulated Protein 78 (GRP78) and a cytokine in the tumor microenvironment. Our research shows that membrane GRP78 is important for drug and immune resistance as well as stem cell formation. Membrane GRP78 has been found on breast, lung, ovarian, prostate, melanoma, multiple myeloma, colon, pediatric and adult brain tumors but not on the surface of normal cells. We have found that membrane GRP78 stabilizes essential cancer supporting oncofetal proteins, ROR1, Cripto, and checkpoint protein, PD-L1, on tumor cell surfaces increasing drug resistance, immune suppression, and cancer stem cell growth. The second pro-tumor factor is a cytokine that is known to induce quiescence in ovarian cancer stem cells. As such, we designed and developed several anti-cancer therapies to specifically block membrane GRP78 from stabilizing pro-tumorigenic proteins on tumor surfaces without disrupting normal cell function. The designed inhibitors will also block the inflammatory cytokine from inducing ovarian stem cell quiescence. Our current lead inhibitor, CBT300, can induce apoptosis of drug-resistant ovarian tumor cells, eliminate drug and immune resistance, induce synergistic effects with chemotherapy and/or immunotherapy, and significantly decrease the amount of chemotherapy needed, thus lowering the toxic side effects. Our Ovarian in vivo mouse study with a GRP78 inhibitor and a cytokine inhibitor displayed a 66% increase in complete tumor regressions with no observable toxicity. A non-toxic therapeutic alternative effective against recurrent drug resistant, quiescent and metastatic ovarian tumors causing complete tumor regressions and increased overall survival and would prove to be paradigm altering. Citation Format: Donald J. Davidson, Rafaela Besse, Jorryn Zelek, Shanuja Jakkala, Mariah Thigpen, Anita K. Davidson. GRP78 and cytokine inhibition displays complete regression of ovarian tumors in mice [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A060.