Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma

Abstract

Glioblastoma (GBM) remains one of the most difficult tumors to treat. The mean overall survival rate of 15 months and the 5-year survival rate of 5% have not significantly changed for almost 2 decades. Despite progress in understanding the pathophysiology of the disease, no new effective treatments to combine with radiation therapy after surgical tumor debulking have become available since the introduction of temozolomide in 1999. One of the main reasons for this is the scarcity of compounds that cross the blood–brain barrier (BBB) and reach the brain tumor tissue in therapeutically effective concentrations. In this review, we focus on the role of the BBB and its importance in developing brain tumor treatments. Moreover, we discuss drug repurposing, a drug discovery approach to identify potential effective candidates with optimal pharmacokinetic profiles for central nervous system (CNS) penetration and that allows rapid implementation in clinical trials. Additionally, we provide an overview of repurposed candidate drug currently being investigated in GBM at the preclinical and clinical levels. Finally, we highlight the importance of phase 0 trials to confirm tumor drug exposure and we discuss emerging drug delivery technologies as an alternative route to maximize therapeutic efficacy of repurposed candidate drug.

UBE2T Promotes Temozolomide Resistance of Glioblastoma Through Regulating the Wnt/β-Catenin Signaling Pathway

“… 5 Although there have been many attempts to improve the efficacy of therapy for GBM, unfortunately, none have achieved the desired therapeutic effect. 6 Therefore, it is of great clinical significance to elucidate the mechanism underlying TMZ resistance and develop new targets for therapeutic intervention.…”

Transferrin-Conjugated PLGA Nanoparticles for Co-Delivery of Temozolomide and Bortezomib to Glioblastoma Cells

“…In recent years different strategies have been explored to circumvent the MGMT resistance, such as the modulation of MGMT expression and/or transcription or directly inactivating the MGMT protein . Different drugs with potential MGMT inhibitory effects have been studied and aligned with the recent investment in drug repurposing strategies for GBM, aiming to identify new uses for already approved drugs …”

“…5 Different drugs with potential MGMT inhibitory effects have been studied and aligned with the recent investment in drug repurposing strategies for GBM, aiming to identify new uses for already approved drugs. 6 One such drug is bortezomib (BTZ), an FDA-approved drug for multiple myeloma treatment 7 that can downregulate MGMT protein expression, leading to increased efficacy of TMZ in GBM patients. 8,9 BTZ blocks the activity of κ-lightchain-enhancer of activated B cells factor (NF-κB), downregulating the MGMT gene expression and enhancing the sensitivity of GBM to TMZ.…”

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

“…The small‐molecular chemotherapeutic agents remain the mainstay of modern GBM drug discovery and development pipeline due to the identification of several known and novel, promising macromolecular targets in GBM‐specific biological pathways (Saraf et al, 2021). A lot of drug repurposing campaigns for GBM against these targets are ongoing, spanning a significant number of similar or GBM‐specific mechanistic perturbations in the complex tumor microenvironment (Lyne & Yamini, 2021; Ntafoulis et al, 2022). Chart 1 lists few representative, chemically‐diverse small‐molecular candidates currently used clinically or undergoing preclinical or clinical investigations for GBM treatment; their molecular targets and anti‐GBM mechanism of action are given in Table 1.…”

“…Chart 1 lists few representative, chemically‐diverse small‐molecular candidates currently used clinically or undergoing preclinical or clinical investigations for GBM treatment; their molecular targets and anti‐GBM mechanism of action are given in Table 1. Interested readers may refer relevant literature (Lyne & Yamini, 2021; Ntafoulis et al, 2022) for more information.…”