Glioblastoma: Current Status, Emerging Targets, and Recent Advances

Abstract

Glioblastoma (GBM) is a highly malignant brain tumor characterized by a heterogeneous population of genetically unstable and highly infiltrative cells that are resistant to chemotherapy. Although substantial efforts have been invested in the field of anti-GBM drug discovery in the past decade, success has primarily been confined to the preclinical level, and clinical studies have often been hampered due to efficacy-, selectivity-, or physicochemical property-related issues. Thus, expansion of the list of molecular targets coupled with a pragmatic design of new small-molecule inhibitors with central nervous system (CNS)-penetrating ability is required to steer the wheels of anti-GBM drug discovery endeavors. This Perspective presents various aspects of drug discovery (challenges in GBM drug discovery and delivery, therapeutic targets, and agents under clinical investigation). The comprehensively covered sections include the recent medicinal chemistry campaigns embarked upon to validate the potential of numerous enzymes/proteins/receptors as therapeutic targets in GBM.

Vanadium(V) Pyridine‐Containing Schiff Base Catecholate Complexes are Lipophilic, Redox‐Active and Selectively Cytotoxic in Glioblastoma (T98G) Cells

“…One of the main challenges for glioblastoma drug development is the design of drug candidates that can cross the blood-brain barrier (BBB), which normally requires them to be small and lipophilic. [2,3] A promising approach to circumvent the impediment of the BBB is to use intratumoral injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor, which represents the next generation of glioblastoma treatments. Such intratumoral injections are currently in Phase I and II human clinical trials for other drugs including platinum-based drugs, such as cisplatin and oxaliplatin, and injections of T-Vec, drugs used to treat advanced melanoma and a range of other cancers.…”

Image‐guided diagnosis and treatment of glioblastoma

“…In addition, drug dose escalation increases the risk of adverse reactions rather than improving therapeutic efficiency. At the same time, the complexity and heterogeneity of GBM are the major factors closely related to multidrug resistance (MDR) in clinical oncology, which hinder the effective tumor suppression of drugs entering intracranial tumors 4a,7 . The development of GBM remains the most severe challenge in terms of diagnosis and therapeutic management due to the deficient accumulation of drugs and drug resistance in intracranial tumor lesions as well as the incomplete resection of tumor tissue.…”

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

“…Glioblastoma (GBM) is the most commonly diagnosed subtype of gliomas and categorized as a grade 4 astrocytoma by the World Health Organization (WHO), accounting for about 57% of all gliomas and 48% of all primary malignant CNS tumors (Tan et al 2020, Thakur et al 2022. The incidence of GBM increases with advancing age, with a peak incidence occurring at 75 to 84 years of age and a slight predominance in men (Grochans et al 2022).…”