Discovering novel therapies for glioma patients

该项目包括TG02和TMZ联合治疗复发性高级别胶质瘤的临床前和临床研究。在临床前研究中，我们对TG02进行了广泛的研究，TG02是一种已知的跨越血脑屏障的新型药物。我们的研究揭示了单剂效应和几种互补的作用机制，这是口服烷化剂替莫唑胺协同作用的基础。我们证明TG02除了通过抑制细胞周期蛋白依赖的激酶9(CDK9)抑制转录外，还通过抑制糖酵解和线粒体功能来降低细胞ATP水平，诱导胶质母细胞瘤细胞死亡，而不是正常星形胶质细胞。联合应用TG02和替莫唑胺可通过抑制糖酵解进一步降低细胞内ATP的生成，这可能是两者协同作用的原因。这种协同作用的进一步特征是在接受TG02和替莫唑胺联合治疗的同基因小鼠胶质母细胞瘤模型中观察到的存活时间延长。总之，TG02针对多种生存机制，与替莫唑胺协同减少能量产生，是治疗难治性胶质母细胞瘤的一种有前景的治疗策略。这些临床前发现为联合疗法的临床测试提供了理论基础，导致了I/II期临床试验的启动(NCT02942264)。I期试验的主要目标是使用剂量密度(Dd)和节律(Mn)方案确定TG02联合TMZ治疗复发高级别星形细胞瘤的最大耐受量(MTD)。第一阶段分两个阶段进行：MTD发现和队列扩大。在TG02在TMZ和两个DO方案(dd和Mn)的联合应用中获得MTDS后，将在每个MTD进行双臂队列扩展，并选择无进展生存期4个月较好的治疗臂作为II期联合治疗臂。在队列扩展阶段计划进行药代动力学、药物遗传学研究和中性粒细胞分析。第二阶段的研究是确定TG02联合TMZ与单独使用TMZ治疗复发的高级别胶质瘤患者的疗效，使用来自第一阶段的剂量。在疾病进展时，被随机分配到对照组的患者将有机会交叉进入治疗组。目前，这项由研究者发起的临床试验的临床前研究已经发表在《临床癌症研究》上。第一阶段研究同时满足主端点和次要端点的要求。一份手稿正在准备中。我们还开展了临床前研究，以确定TG02治疗胶质瘤的耐药机制，以及部分胶质瘤对TG02治疗的选择性易感性。第一阶段研究已经完成并发表。

This project includes both preclinical and clinical studies of the combination of TG02 and TMZ in recurrent high-grade gliomas. In the preclinical studies, we extensively investigated TG02, a novel agent known to cross the blood-brain barrier. Our investigations uncovered the single agent effect and several complementary mechanisms of action that underlie the synergy with an oral alkylating agent, temozolomide. We demonstrated that in addition to suppressing transcription through inhibition of cyclin-dependent kinase 9 (CDK9), TG02 also decreases cellular ATP levels by suppression of glycolysis and mitochondrial function, inducing cell death in glioblastoma cells but not in normal astrocytes. Cellular ATP production is further decreased with the combined treatment of TG02 and temozolomide by inhibiting glycolysis, which could explain the synergistic effects. The synergy is further characterized by a prolonged survival that was observed in a syngeneic mouse glioblastoma model receiving combined treatment of TG02 and temozolomide. In summary, TG02 targets multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in refractory glioblastoma. The findings in these preclinical findings, providing the rationale for clinical testing of the combination therapy, have led to the launching of phase I/II clinical trial (NCT02942264). The primary objective of Phase I trial is to determine the maximum tolerate dose (MTD) of TG02 plus TMZ using both dose-dense (dd) and metronomic (mn) schedules in adult patients with recurrent high-grade astrocytoma. The phase I part is conducted in two stages: the MTD finding and cohort expansion. After MTDs of TG02 in a combination of TMZ with two doing schedules (dd and mn) are obtained, the cohort expansion of both arms will be performed at each MTD and the treatment arm with a better progression-free survival at 4 months will be selected for the combination treatment arm for phase II. Pharmacokinetic, pharmacogenetic studies and neutrophil analysis are planned during the cohort expansion phase. The phase II study is to determine the efficacy of TG02 plus TMZ versus TMZ alone in the recurrent high-grade glioma patients, using the dosage that is derived from the phase I part. At the disease progression, patients that are randomized to control arm will be offered the opportunity to cross-over to the treatment arm. Currently, the preclinical studies that let to this investigator-initiated clinical trial have been published in Clinical Cancer Research. Both primary and secondary endpoints are met for the phase 1 study. A manuscript is in preparation. We have also developed preclinical research to identify the resistance mechanisms of TG02 in treating gliomas and the selective vulnerability of a subset of glioma to TG02 treatment. Phase 1 study has been completed and published.