Bench to bedside radiosensitizer development strategy for newly diagnosed glioblastoma

Abstract

Glioblastoma is the most common primary brain malignancy and carries with it a poor prognosis. New agents are urgently needed, however nearly all Phase III trials of GBM patients of the past 25 years have failed to demonstrate improvement in outcomes. In 2019, the National Cancer Institute Clinical Trials and Translational Research Advisory Committee (CTAC) Glioblastoma Working Group (GBM WG) identified 5 broad areas of research thought to be important in the development of new herapeutics for GBM. Among those was optimizing radioresponse for GBM in situ. One such strategy to increase radiation efficacy is the addition of a radiosensitizer to improve the therapeutic ratio by enhancing tumor sensitivity while ideally having minimal to no effect on normal tissue. Historically the majority of trials using radiosensitizers have been unsuccessful, but they provide important guidance in what is required to develop agents more efficiently. Improved target selection is essential for a drug to provide maximal benefit, and once that target is identified it must be validated through pre-clinical studies. Careful selection of appropriate in vitro and in vivo models to demonstrate increased radiosensitivity and suitable bioavailability are then necessary to prove that a drug warrants advancement to clinical investigation. Once investigational agents are validated pre-clinically, patient trials require consistency both in terms of planning study design as well as reporting efficacy and toxicity in order to assess the potential benefit of the drug. Through this paper we hope to outline strategies for developing effective radiosensitizers against GBM using as models the examples of XPO1 inhibitors and HDAC inhibitors developed from our own lab.

Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma

“…However, transfer to clinical application is difficult as unacceptable toxicity or bioavailability in the central nervous system (CNS) can be limiting factors [ 47 ]. Although the blood-brain barrier (BBB) is considered locally disrupted in GB, the disease occultly infiltrates the brain tissue [ 5 , 48 ].…”

Quisinostat is a brain-penetrant radiosensitizer in glioblastoma

“…Identification of drugs that can enhance the effects of radiation treatment is an intense area of research within neuro-oncology, especially for patients with MGMT -unmethylated tumors. Nevertheless, although the use of radiosensitizers represents a promising strategy in GBM, the development of these novel agents has been underwhelming ( 81 ). Here, we provide the first preclinical report to our knowledge for a brain-penetrant HDACi, QST, with potent radiosensitizing properties.…”

Combining a noble gas with radiotherapy: Glutamate receptor antagonist xenon acts as a radiosensitizer in glioblastoma

“…In vitro data have, so far, shown radiosensitizing potential for the NMDAR-inhibitors ifenprodil, dizocilpine, riluzole and memantine (17,19). However, transfer to clinical application is di cult as unacceptable toxicity or bioavailability in the central nervous system (CNS) can be limiting factors (49). Although the BBB is considered locally disrupted in GB, the disease occultly in ltrates the brain tissue (5,50).…”