A Novel Class of Radiosensitizers for Glioblastoma

Oncotarget published "Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore" which reported that this group previously identified a calcium channel blocker, mibefradil, as a potential GBM radiosensitizer. They discovered that mibefradil selectively inhibits a key DNA repair pathway, alternative non-homologous end joining.

Then, they initiated a phase I clinical trial that revealed promising initial efficacy of mibefradil, but further development was hampered by dose-limiting toxicities, including CCB-related cardiotoxicity, off-target hERG channel and cytochrome P450 enzymes interactions.

Here, the authors show that mibefradil inhibits DNA repair independent of its CCB activity, and report a series of mibefradil analogues which lack CCB activity and demonstrate reduced hERG and CYP activity while retaining potency as DNA repair inhibitors. They also report a targeted siRNA-based screen which suggests a possible role for mTOR and Akt in DNA repair inhibition by this class of drugs.

Taken together, these Oncotarget data reveal a new class of mibefradil-based DNA repair inhibitors which can be further advanced into pre-clinical testing and eventually clinical trials, as potential GBM radiosensitizers.

Dr. Yulia V. Surovtseva and Dr. Ranjit S. Bindra from Yale University said, "Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system (CNS)."

Cells utilize several DNA double-strand break repair pathways to repair DNA damage induced by irradiation.

This pathway repairs only 0.5–1% of total DSBs, but serves as a crucial back-up pathway for both NHEJ and HR and for the repair of complex DNA lesions arising from IR-induced damage.

The EJ-DR assay was utilized in a high-throughput chemical screen for novel DNA repair inhibitors, which identified the T-type and L-type calcium channel blocker, mibefradil, as a selective inhibitor of alt-NHEJ repair.

Based on these findings, the authors sought to create a new class of radiosensitizers which retained mibefradil's activity as a DNA repair inhibitor, but showed reduced hERG and CYP450 enzyme inhibition.

Finally, through the knockdown of DNA damage response proteins in the high-throughput imaging-based assay, we identified potential targets or regulators of mibefradil, which phenocopied the selective inhibition of alt-NHEJ over HR.

The Surovtseva/Bindra Research Team concluded in their Oncotarget Research Output that, the use of DNA repair inhibitors as radiosensitizers in GBM could represent a viable approach to achieve better response owing to the range of DDR pathways activated in response to radiation-induced DNA damage.

Additionally, the identification of selective inhibitors of alt-NHEJ could also be tested in other settings where alt-NHEJ activity is critical, such as in HR-deficient tumors.

The synthesis and validation of the mibefradil analogue, YU252386, shows great promise towards the development of a potent and selective radiosensitizer for GBMs and beyond, and warrants further in vivo study in clinically relevant GBM models.

Reference: Paradkar S, Herrington J, Hendricson A, et al. Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore. Oncotarget. 2021;12(9):891-906. doi: 10.18632/oncotarget.27933

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