Neuropharmacological Study of Posaconazole for Glioblastoma: A Phase 0 Clinical Trial Protocol.
Neuropharmacological Study of Posaconazole for Glioblastoma: A Phase 0 Clinical Trial Protocol.
复制标题
DOI：
10.1227/neu.0000000000002071
复制
发表时间：
2022-07
期刊：
影响因子：
4.8
通讯作者：
D. Bhanja;J. Neighbors;J. Connor;G. Zadeh;A. Mansouri
中科院分区：
文献类型：
--
作者：
D. Bhanja;J. Neighbors;J. Connor;G. Zadeh;A. Mansouri
背景胶质母细胞瘤（GBM）是最常见的恶性原发性脑肿瘤，预后普遍较差。GBM表达升高水平的己糖激酶2（HK 2），催化糖酵解的关键步骤，并影响几个致癌途径。先前的临床前工作表明，重新利用泊沙康唑（PCZ）在下调HK 2活性、减少乳酸和丙酮酸产生、干扰肿瘤细胞代谢和增加小鼠存活率方面的作用。目的建立PCZ在成人GBM中的脑肿瘤转移率、神经药代动力学特征以及对肿瘤细胞代谢的机制作用。方法：这是一项涉及GBM患者的开放标签、非随机、平行组试验。队列将接受PCZ（干预，n = 5）或不接受PCZ（对照，n = 5），随后进行肿瘤切除和微透析导管放置。将分析透析液、血浆和肿瘤样本的乳酸盐和丙酮酸盐浓度。还将评估肿瘤样本的PCZ浓度、HK 2表达、血管生成和细胞凋亡。将根据脑皮质中PCZ浓度的浓度-时间曲线和0 - 24小时曲线下面积确定PCZ的神经药代动力学。预期结果（1）与非增强区域相比，增强脑区域中的PCZ浓度增加;（2）随着时间的推移，接受治疗患者透析液样本中乳酸/丙酮酸与PCZ浓度呈负相关;（3）接受PCZ治疗的肿瘤样本中HK 2活性降低。讨论一个成功的试验将支持进行高级阶段试验的决定。PCZ的任何肿瘤渗透，伴随着对糖酵解的影响，都需要进一步深入分析，因为这些致命肿瘤的治疗选择目前有限。
BACKGROUND Glioblastoma (GBM) is the most common malignant primary brain tumor with a universally poor prognosis. GBMs express elevated levels of hexokinase 2 (HK2), catalyzing the critical step in glycolysis and influencing several oncogenic pathways. Previous preclinical work has suggested a role for repurposed posaconazole (PCZ) in downregulating HK2 activity, reducing lactate and pyruvate production, interfering with tumor cell metabolism, and increasing mouse survival. OBJECTIVE To establish brain tumor penetrance, neuropharmacokinetic profile, and mechanistic effect on tumor cell metabolism of PCZ in adults with GBM. METHODS This is an open label, nonrandomized, parallel arm trial involving patients with GBM. Cohorts will receive PCZ (intervention, n = 5) or will not receive PCZ (control, n = 5), followed by tumor resection and microdialysis catheter placement. Dialysate, plasma, and tumor samples will be analyzed for lactate and pyruvate concentrations. Tumor samples will also be assessed for PCZ concentration, HK2 expression, angiogenesis, and apoptosis. PCZ's neuropharmacokinetics will be determined based on the concentration vs time profile and area under the curve 0 to 24 hours of PCZ concentration in the brain interstitium. EXPECTED OUTCOMES (1) Increased PCZ concentration in contrast-enhancing brain regions compared with nonenhancing regions; (2) inverse correlation between lactate/pyruvate and PCZ concentrations in dialysate samples from treated patients, over time; and (3) decreased HK2 activity in PCZ-treated tumor samples. DISCUSSION A successful trial will support the decision to proceed to advanced phase trials. Any tumor penetration by PCZ, with concomitant effect on glycolysis, warrants further in-depth analysis, as therapeutic options for these deadly tumors are currently limited.