Central Nervous System Delivery of the Catalytic Subunit of DNA-Dependent Protein Kinase Inhibitor Peposertib as Radiosensitizer for Brain Metastases

Surabhi Talele; Wenjuan Zhang; Ju-Hee Oh; Danielle M. Burgenske; Ann C. Mladek; Sonja Dragojevic; Jann N. Sarkaria; William F. Elmquist

doi:10.1124/jpet.121.001069

Abstract

Cytotoxic effects of chemotherapy and radiation therapy (RT) used for the treatment of brain metastases results from DNA damage within cancer cells. Cells rely on highly evolved DNA damage response (DDR) pathways to repair the damage caused by these treatments. Inhibiting these repair pathways can further sensitize cancer cells to chemotherapy and RT. The catalytic subunit of DNA-dependent protein kinase, in a complex with Ku80 and Ku70, is a pivotal regulator of the DDR, and peposertib is a potent inhibitor of this catalytic subunit. The characterization of central nervous system (CNS) distributional kinetics of peposertib is critical in establishing a therapeutic index in the setting of brain metastases. Our studies demonstrate that the delivery of peposertib is severely restricted into the CNS as opposed to peripheral organs, by active efflux at the blood-brain barrier (BBB). Peposertib has a low free fraction in the brain and spinal cord, further reducing the active concentration, and distributes to the same degree within different anatomic regions of the brain. However, peposertib is heterogeneously distributed within the metastatic tumor, where its concentration is highest within the tumor core (with disrupted BBB) and substantially lower within the invasive tumor rim (with a relatively intact BBB) and surrounding normal brain. These findings are critical in guiding the potential clinical deployment of peposertib as a radiosensitizing agent for the safe and effective treatment of brain metastases.

SIGNIFICANCE STATEMENT Effective radiosensitization of brain metastases while avoiding toxicity to the surrounding brain is critical in the development of novel radiosensitizers. The central nervous system distribution of peposertib, a potent catalytic subunit of DNA-dependent protein kinase inhibitor, is restricted by active efflux in the normal blood-brain barrier (BBB) but can reach significant concentrations in the tumor core. This finding suggests that peposertib may be an effective radiosensitizer for intracranial tumors with an open BBB, while limited distribution into normal brain will decrease the risk of enhanced radiation injury.

Footnotes

Received December 21, 2021.
Accepted March 21, 2022.

This work was supported by National Institutes of Health National Cancer Institute [Grant RO1-CA138437], [Grant U54-CA210181], [Grant U01-CA227954], and [Grant P50-CA108960] and National Institute of Neurological Disorders and Stroke [Grant RO1-NS077921] (to J.N.S. and W.F.E). This research was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755), who provided peposertib through the Cancer Therapy Evaluation Program (CTEP) of the NCI. S.T. was supported by the Rory P. Remmel and Cheryl L. Zimmerman fellowship in Drug Metabolism and Pharmacokinetics, Edward G. Rippie fellowship, Bighley Graduate fellowship, Ronald J. Sawchuk fellowship in Pharmacokinetics, and Doctoral Dissertation fellowship.
No author has an actual or perceived conflict of interest with the contents of this article.
https://doi.org/10.1124/jpet.121.001069.
↵This article has supplemental material available at jpet.aspetjournals.org.