Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., S.T., W.Q.Z., W.F.E.) and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., S.D., D.M.B., K.K.B., B.L.C., M.A.C., L.H., Z.H., J.N.S.)
Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., S.T., W.Q.Z., W.F.E.) and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., S.D., D.M.B., K.K.B., B.L.C., M.A.C., L.H., Z.H., J.N.S.).
J Pharmacol Exp Ther. 2024 Oct 18;391(2):346-360. doi: 10.1124/jpet.123.002002.
Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro-in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. SIGNIFICANCE STATEMENT: This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and central nervous system (CNS) distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in glioblastoma (GBM) patient-derived xenograft (PDX) models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM or other CNS tumors.
胶质母细胞瘤（GBM）是一种累及全脑的疾病，其浸润性肿瘤细胞受到完整血脑屏障（BBB）的保护。尽管采用了积极的治疗方法，GBM 的预后仍较差，部分原因是 BBB 处的药物通透性不足。目前的标准治疗方案包括放疗和细胞毒性化疗，这些治疗方法会导致 DNA 损伤。随后，DNA 损伤反应（DDR）通路的激活会诱导耐药性。目前正在探索各种 DDR 抑制剂作为放疗和化疗增敏剂，这些抑制剂靶向这些通路的关键调节因子，如共济失调毛细血管扩张突变和 Rad3 相关（ATR）。新型 ATR 激酶抑制剂 elimusertib 可阻止受损 DNA 的修复，从而提高 DNA 损伤细胞毒性治疗的疗效。体外研究观察到 elimusertib 与 DNA 损伤剂替莫唑胺联合使用时具有强大的协同作用；然而，我们在 GBM 原位荷瘤小鼠的体内疗效研究中并未观察到这种联合治疗的改善。为了了解影响 elimusertib 中枢神经系统（CNS）分布和缺乏疗效的因素，我们对这种体外-体内不匹配进行了探索。我们观察到 elimusertib 在小鼠体内的系统循环中迅速清除，并且无法在 CNS 中维持足够的暴露量，以实现与替莫唑胺有效的联合治疗。elimusertib 在 CNS 中的分布部分受到 BBB 上 P-糖蛋白外排的限制，并且与 CNS 组织的高结合导致大脑中具有药理活性（未结合）的药物水平较低。考虑到药代动力学种间差异的可能性，这些数据表明，临床中可能限制了 elimusertib 与替莫唑胺联合治疗 GBM 的应用。意义声明：本研究通过探索系统和中枢神经系统（CNS）分布药代动力学，研究了 elimusertib/替莫唑胺联合治疗的体外协同作用和体内疗效之间的不匹配。结果表明，在胶质母细胞瘤（GBM）患者来源异种移植（PDX）模型中，联合治疗的疗效没有改善，这可能归因于 CNS 中具有药理活性的药物浓度暴露不足。这些观察结果可以指导进一步探索 elimusertib 治疗 GBM 或其他 CNS 肿瘤。
