Jensen Katharine Victoria, Cseh Orsolya, Aman Ahmed, Weiss Samuel, Luchman Hema Artee
Hotchkiss Brain Institute and Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta, Canada.
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
PLoS One. 2017 Dec 18;12(12):e0189670. doi: 10.1371/journal.pone.0189670. eCollection 2017.
The prognosis for patients diagnosed with glioblastoma multiforme (GBM) remains dismal, with current treatment prolonging survival only modestly. As such, there remains a strong need for novel therapeutic strategies. The janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathway regulates many cellular processes in GBM, including survival, proliferation, invasion, anti-apoptosis, and immune evasion. Here, we evaluated the preclinical efficacy of pacritinib, a novel compound targeting JAK2, using a collection of diverse patient-derived brain tumor initiating cells (BTICs).
The effects of pacritinib on BTIC viability and sphere forming capacity were evaluated in vitro using the alamarBlue and neurosphere assays, respectively. On-target inhibition of JAK2/STAT3 signaling was investigated using western blotting. The efficacy of pacritinib was tested in vivo in pharmacokinetic analyses, liver microsome analyses, and Kaplan-Meier survival studies.
In vitro, pacritinib decreased BTIC viability and sphere forming potential at low micromolar doses and demonstrated on-target inhibition of STAT3 signaling. Additionally, pacritinib was found to improve the response to temozolomide (TMZ) in TMZ-resistant BTICs. In vivo, systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture.
This preclinical study demonstrates the efficacy of pacritinib and supports the feasibility of testing pacritinib for the treatment of GBM, in combination with the standard of care TMZ.
多形性胶质母细胞瘤（GBM）患者的预后仍然很差，目前的治疗方法仅能适度延长生存期。因此，迫切需要新的治疗策略。Janus激酶（JAK）2/信号转导和转录激活因子（STAT）3通路调节GBM中的许多细胞过程，包括存活、增殖、侵袭、抗凋亡和免疫逃逸。在此，我们使用多种患者来源的脑肿瘤起始细胞（BTIC）评估了新型JAK2靶向化合物帕西替尼的临床前疗效。
分别使用alamarBlue和神经球试验在体外评估帕西替尼对BTIC活力和球形成能力的影响。使用蛋白质印迹法研究JAK2/STAT3信号的靶向抑制。在药代动力学分析、肝微粒体分析和Kaplan-Meier生存研究中对帕西替尼的疗效进行体内测试。
在体外，帕西替尼在低微摩尔剂量下降低了BTIC活力和球形成潜力，并显示出对STAT3信号的靶向抑制。此外，发现帕西替尼可改善对替莫唑胺（TMZ）耐药的BTIC对TMZ的反应。在体内，用帕西替尼进行全身治疗显示可穿透血脑屏障，并与TMZ联合使用可提高原位移植侵袭性复发性GBM BTIC培养物的小鼠的总体中位生存期。
这项临床前研究证明了帕西替尼的疗效，并支持测试帕西替尼与标准治疗药物TMZ联合治疗GBM的可行性。
