Oncotarget: Creation of a new 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.

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.

###

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DOI

–

https:/

/

doi.

org/

10.

18632/

oncotarget.

27933

Full text

–

https:/

/

www.

oncotarget.

com/

article/

27933/

text/

Correspondence to

– Yulia V. Surovtseva –

[email protected]

and Ranjit S. Bindra –

[email protected]

Keywords

–


lioblastoma

,

radiosensitizers

,

mibefradil

,

DNA repair

,

alternative non-homologous end joining

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Oncotarget

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