Satterlee Andrew B, Dunn Denise E, Valdivia Alain, Malawsky Daniel, Buckley Andrew, Gershon Timothy, Floyd Scott, Hingtgen Shawn
Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27704, USA.
Mol Ther Oncolytics. 2022 Jun 7;26:49-62. doi: 10.1016/j.omto.2022.06.004. eCollection 2022 Sep 15.
Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM); however, treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaptation of GBM during treatment with human skin-derived induced NSCs releasing the pro-apoptotic agent TRAIL (iNSC-TRAIL) and develop strategies that convert initial tumor kill into sustained GBM suppression. and analysis before, during, and after treatment revealed significant shifts in tumor transcriptome and spatial distribution as the tumors adapted to treatment. To address this, we designed iNSC delivery strategies that increased spatiotemporal TRAIL coverage and significantly decreased GBM volume throughout the brain, reducing tumor burden 100-fold as quantified in live brain slices. The varying impact of different strategies on treatment durability and median survival of both solid and invasive tumors provides important guidance for optimizing iNSC therapy.
基因工程神经干细胞（NSCs）是治疗极具侵袭性的脑癌胶质母细胞瘤（GBM）的一种很有前景的疗法；然而，治疗的持久性仍然是一个重大挑战。我们试图确定在用释放促凋亡剂TRAIL的人皮肤来源诱导神经干细胞（iNSC-TRAIL）治疗GBM期间促成其动态适应的事件，并制定将初始肿瘤杀伤转化为持续抑制GBM的策略。治疗前、治疗期间和治疗后的 分析显示，随着肿瘤适应治疗，肿瘤转录组和空间分布发生了显著变化。为了解决这个问题，我们设计了iNSC递送策略，增加了时空TRAIL覆盖范围，并显著减小了全脑GBM的体积，在活脑切片中定量显示肿瘤负担降低了100倍。不同策略对实体瘤和侵袭性肿瘤治疗持久性和中位生存期的不同影响为优化iNSC治疗提供了重要指导。
