Department of Pharmaceutics, Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.T., W.Z., J.-H.O., W.F.E.) and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.M.B., A.C.M., S.D., J.N.S.).
Department of Pharmaceutics, Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.T., W.Z., J.-H.O., W.F.E.) and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.M.B., A.C.M., S.D., J.N.S.)
J Pharmacol Exp Ther. 2022 Jun;381(3):217-228. doi: 10.1124/jpet.121.001069. Epub 2022 Apr 3.
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.
化疗和放疗（RT）用于治疗脑转移的细胞毒性作用源于癌细胞内的 DNA 损伤。细胞依赖高度进化的 DNA 损伤反应（DDR）途径来修复这些治疗引起的损伤。抑制这些修复途径可以进一步使癌细胞对化疗和 RT 敏感。DNA 依赖性蛋白激酶的催化亚基与 Ku80 和 Ku70 形成复合物，是 DDR 的关键调节剂，而 peposertib 是该催化亚基的有效抑制剂。 peposertib 在中枢神经系统（CNS）中的分布动力学特征对于在脑转移的情况下建立治疗指数至关重要。我们的研究表明，与外周器官相比，peposertib 通过血脑屏障（BBB）的主动外排，严重限制了其向中枢神经系统的传递。peposertib 在大脑和脊髓中的游离分数较低，进一步降低了活性浓度，并在大脑的不同解剖区域内以相同程度分布。然而，peposertib 在转移性肿瘤内分布不均匀，其浓度在肿瘤核心（BBB 破裂）最高，在侵袭性肿瘤边缘（相对完整的 BBB）和周围正常脑组织中显著降低。这些发现对于指导 peposertib 作为放射增敏剂在安全有效地治疗脑转移瘤中的潜在临床应用具有重要意义。
有效放射增敏脑转移瘤，同时避免对周围脑组织的毒性作用，是开发新型放射增敏剂的关键。强效 DNA 依赖性蛋白激酶抑制剂 peposertib 的中枢神经系统分布受正常血脑屏障（BBB）中的主动外排限制，但可在肿瘤核心达到显著浓度。这一发现表明，peposertib 可能是 BBB 开放的颅内肿瘤的有效放射增敏剂，而其向正常脑组织的有限分布将降低增强放射损伤的风险。
