Abstract 4484: Targeting DNA repair mechanism that leverages current standard of care interventions with a novel agent in glioma

Abstract Glioblastoma (GBM) is a malignant glioma characterized by molecular heterogeneity and poor prognosis. GBM remains a uniformly lethal malignancy, with patient survival rarely exceeding two years despite the best available treatments. In clinical practice, about 60% of GBM patients have shown overexpression of O6-methylguanine-methyl-transferase (MGMT), an enzyme responsible for DNA repair, were found to receive little benefit from TMZ and represent a group of great unmet need with no chemotherapeutic agents that significantly improve survival. A key factor contributing to treatment resistance and disease relapse is the overexpression of MGMT. MGMT overexpression reduces the efficacy of standard therapies like temozolomide (TMZ) and radiotherapy (RT), leaving patients with active MGMT expressions in urgent need of new treatment strategies. The depletion of MGMT in tumors has been investigated as a strategy to increase TMZ and RT efficacies in resistant, MGMT-positive GBMs. Chemical depletion using O6-benzylguanine derivatives as MGMT inhibitors have been actively tested, but these compounds are associated with high hematologic toxicity. Recent studies have shown that disulfiram (DSF), an alcohol aversion drug, combined with copper (Cu), can inhibit MGMT and improve the response to TMZ in GBM. However, phase II clinical trials using oral Cu/DSF demonstrated no survival benefit, primarily due to the instability of DSF in vivo. To address this limitation, we developed a novel delivery system using 2-hydroxypropyl beta cyclodextrin (HPßCD) encapsulating the Cu complex of DSF's active metabolite, diethyldithiocarbamic acid (DDC). This HPßCD-Cu(DDC)2formulation stabilizes the complex, preventing degradation and reducing non-specific interactions in the bloodstream. In vitro studies revealed that HPßCD-Cu(DDC)2 inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell cultures vastly increased the alkylation-induced DNA double-strand breaks (gama-H2AX), that are hallmark of TMZ effectiveness as supported by cytotoxicity and the increased levels of apoptotic markers, like JNK-P and cleavage of PARP-1. Systemic delivery of HPßCD-Cu(DDC)2 in MGMT overexpressed patient derived orthotropic xenograft resulted in depletion of MGMT with tumor size regression. Tumor burden has been evaluated within patient derived orthotropic rat models that represent high expression of MGMT followed by oral vs intravenous treatments. Citation Format: Meser M. Ali, Hamid Suhail, Mahesh Yadab, Ataur Rahman, James Snyder. Targeting DNA repair mechanism that leverages current standard of care interventions with a novel agent in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4484.