A novel delivery system using 2-hydroxypropyl beta cyclodextrin () encapsulating Cu(DDC) may improve treatment efficacy for glioblastoma (GBM).
Glioblastoma is associated with a survival of less than 2 years despite current therapies.
Overexpression of the enzyme is linked to poor response to temozolomide (TMZ) and radiotherapy in GBM patients.
Disulfiram (DSF) has shown potential to inhibit MGMT and enhance the effectiveness of TMZ when combined with copper.
Oral delivery of Cu/DSF did not yield significant survival benefits in a phase II trial.
HPβCD was found to stabilize Cu(DDC) and inhibit MGMT through a specific cellular pathway.
Preliminary results indicated that HPβCD-Cu(DDC) in combination with TMZ may lead to tumor size regression in a patient-derived xenograft model.
Simplified
The uniform lethality of glioblastoma (GBM) with a survival of less than 2 years despite best available therapy is attributed to treatment resistance due to DNA repair mechanisms that drive disease relapse and tumor heterogeneity. One prognostic factor identified as a reliable biomarker for GBM sensitivity to temozolomide (TMZ) and radiotherapy (RT) is the overexpression of O-methylguanine-methyl-transferase () enzyme. Patients with active MGMT were found to receive little benefit from TMZ and RT. They represent a group of great unmet need with no treatment options that significantly improve survival. Recently, several preclinical and clinical studies suggest that the alcohol aversion drug, disulfiram (DSF), inhibited MGMT and improved the efficacy of TMZ in GBM when combined with copper (Cu). However, phase II trial showed that there was no significant survival benefit from oral Cu/DSF. Nevertheless, the major limitation of oral Cu/DSF has been delivery of fragile DSF to the in vivo system. To address this limitation, we developed a novel delivery system using 2-hydroxypropyl beta cyclodextrin () encapsulating the Cu complex of DSF's active metabolite, diethyldithiocarbamic acid (DDC). It was determined that HPβCD stabilized Cu(DDC). In vitro cell culture study revealed that HPβCD-Cu(DDC)inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell cultures vastly increased the alkylation-induced DNA double-strand breaks, cytotoxicity, and the levels of apoptotic markers like histone family member X (γ-H2AX), JNK-P and cleavage of Poly [ADP-ribose] polymerase 1 (PARP-1). Preliminary intravenous delivery of HPβCD-Cu(DDC)in combination with TMZ in an MGMT-positive patient derived orthotopic xenograft (PDOX) model demonstrated tumor size regression. HPβCD-Cu(DDC)targets MGMT-145-cysteine and its unique cytotoxic mechanism circumvents MGMT-mediated TMZ resistance. This novel delivery system shows promise for overcoming MGMT-mediated resistance in GBM, offering a potential new therapeutic strategy. 6 2 2 2 2
Key numbers
significantly smaller
Tumor Size Reduction
Compared to control or TMZ treatment alone
80–90%
Cell Viability Reduction
Cell viability remained high even at 200 µM TMZ
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Declarations. Competing interests: The authors declare no competing interests. Henry Ford Health has received travel compensation on behalf of JMS for presentations not related to this work by Hoffmann-La Roche AG and Premier Applied Sciences.
