Thang Morrent, Mellows Clara, Kass Lauren E, Daglish Sabrina, Fennell Emily M J, Mann Breanna E, Mercer-Smith Alison R, Valdivia Alain, Graves Lee M, Hingtgen Shawn D
Neuroscience Center, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina-Chapel Hill School of Pharmacy, Chapel Hill, NC, USA.
Mol Ther Oncol. 2024 Jun 15;32(3):200834. doi: 10.1016/j.omton.2024.200834. eCollection 2024 Sep 19.
Tumor-homing neural stem cell (NSC) therapy is emerging as a promising treatment for aggressive cancers of the brain. Despite their success, developing tumor-homing NSC therapy therapies that maintain durable tumor suppression remains a challenge. Herein, we report a synergistic combination regimen where the novel small molecule TR-107 augments NSC-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy (hiNeuroS-TRAIL) in models of the incurable brain cancer glioblastoma (GBM) . We report that the combination of hiNeuroS-TRAIL and TR-107 synergistically upregulated caspase markers and restored sensitivity to the intrinsic apoptotic pathway by significantly downregulating inhibitory pathways associated with chemoresistance and radioresistance in the TRAIL-resistant LN229 cell line. This combination also showed robust tumor suppression and enhanced survival of mice bearing human xenografts of both solid and invasive GBMs. These findings elucidate a novel combination regimen and suggest that the combination of these clinically relevant agents may represent a new therapeutic option with increased efficacy for patients with GBM.
肿瘤归巢神经干细胞（NSC）疗法正成为一种治疗侵袭性脑癌的有前景的方法。尽管取得了成功，但开发能持续抑制肿瘤的肿瘤归巢NSC疗法仍然是一项挑战。在此，我们报告一种协同联合方案，其中新型小分子TR-107在无法治愈的脑癌胶质母细胞瘤（GBM）模型中增强了NSC-肿瘤坏死因子相关凋亡诱导配体（TRAIL）疗法（hiNeuroS-TRAIL）。我们报告，hiNeuroS-TRAIL和TR-107的联合协同上调了半胱天冬酶标志物，并通过显著下调与TRAIL耐药性LN229细胞系中化学抗性和放射抗性相关的抑制途径，恢复了对内在凋亡途径的敏感性。这种联合还显示出强大的肿瘤抑制作用，并提高了携带实体和侵袭性GBM人异种移植瘤小鼠的存活率。这些发现阐明了一种新型联合方案，并表明这些临床相关药物的联合可能代表一种对GBM患者疗效更高的新治疗选择。
