Discovering novel therapies for glioma patients

基于我们之前在高级别恶性胶质瘤的临床前和临床工作，FDA授予ZOT治疗恶性胶质瘤的孤儿药资格。基于先前临床研究的观察结果，我们继续研究ZOT在神经胶质瘤亚群中的选择性作用。这个正在进行的项目包括ZOT在idh突变胶质瘤中的临床前和临床研究。在临床前研究中，我们在IDH突变型和野生型胶质瘤模型中测试了ZOT的反应。我们证明了与idh野生型肿瘤相比，idh突变胶质瘤对ZOT的敏感性增加。与IDH野生型胶质瘤细胞相比，IDH突变细胞的IC50在患者来源的GSC系和具有或不具有IDH突变的等基因小鼠细胞中被证明较低。在突变型细胞中，低剂量的ZOT能够通过抑制细胞周期蛋白依赖性激酶9 （CDK9）和RNAPOL II来抑制转录，而在野生型细胞中则没有。在低剂量zot治疗的IDH突变型胶质瘤中也可见细胞凋亡、线粒体功能障碍和ATP减少，但在IDH野生型肿瘤中未见。单药ZOT在idh突变型胶质瘤小鼠模型中有显著的生存益处，而在野生型胶质瘤模型中没有。基于临床前研究结果，我们假设idh突变胶质瘤由于其独特的肿瘤生物学特性而增加了对ZOT的敏感性。idh突变胶质瘤患者的单药ZOT将改善临床结果，包括生存益处和更少的毒性。为了在临床试验中验证这一假设，我设计了一项针对idh突变胶质瘤患者的临床试验。题为“左替拉西尼治疗复发性高级别胶质瘤异柠檬酸脱氢酶1或2 （IDH1或IDH2）突变的I/II期研究”。在I期部分，主要目标是估计ZOT的推荐II期剂量（RP2D）。在II期研究中，主要目标是确定接受ZOT治疗的复发性胶质瘤、idh1 /2突变体、世界卫生组织（WHO） 3级患者的12个月无进展生存期（PFS），并与已建立的脑肿瘤数据库进行比较，以匹配肿瘤分子特征和临床预后因素。在第二阶段，我们建立了一个外科队列。手术队列的参与者将在第0周期的第1天在RP2D接受一剂研究药物的额外单次预处理，随后在24小时内进行脑肿瘤活检或手术切除。手术样本将用于PK和PD分析，以确定研究药物在肿瘤中的药物暴露和生物学效应。更重要的是，我们计划使用md安德森症状清单-脑肿瘤（MDASI-BT）或md安德森症状清单-脊柱模块（MDASI-SP）仪器，通过自我报告的症状严重程度和对日常活动的干扰，对参与者报告的结果（PRO）进行纵向评估。这将评估患者在接受肿瘤控制治疗时的症状负担和生活质量。最后，接受ZOT的参与者的药理学（PG）特征将被确定并与治疗反应和毒性相关。这项1期研究的结果已经完成并发表。

Based on our previous preclinical and clinical works in high-grade malignant gliomas, FDA granted the orphan drug designation for ZOT in malignant gliomas treatment. Based on the observations from the previous clinical study, we continued to investigate the selective effect of ZOT in a subset of gliomas. This ongoing project includes both preclinical and clinical studies of ZOT in IDH-mutant gliomas. In the preclinical studies, we tested the responses to ZOT in both IDH mutant and wildtype glioma models. We demonstrated the increased sensitivity to ZOT in IDH-mutant gliomas compared to the IDH-wildtype tumor. A lower IC50 in IDH-mutant cells compared to the IDH-wildtype glioma cells was demonstrated in patient-derived GSC lines and isogenic mouse cells with and without IDH mutation. A lower dose of ZOT was able to suppress transcription through inhibition of cyclin-dependent kinase 9 (CDK9) and RNAPOL II in mutant cells but not in wild-type cells. Apoptosis, mitochondrial dysfunction and ATP reduction are also seen in low dose ZOT-treated IDH-mutant gliomas but not in IDH wildtype tumors. A significant survival benefit of single-agent ZOT is observed in mouse model of IDH-mutant but not wild-type gliomas. Based on the preclinical findings, we hypothesized that IDH-mutant glioma has increased sensitivity to ZOT due to its unique tumor biology. Single-agent ZOT in patients with IDH-mutant gliomas will improve clinical outcomes, including survival benefits and less of toxicities. To test the hypothesis in the clinical trial setting, I have designed a clinical trial in IDH-mutant glioma patients. Entitled "A Phase I/II Study of Zotiraciclib for Recurrent High-Grade Gliomas with Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations". In Phase I part, the primary objective is to estimate recommended phase II dose (RP2D) of ZOT. In Phase II, the primary objective is to determine 12-month progression-free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with ZOT in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors. In the phase II part, we built a surgical cohort. Participants in the surgical cohort will get an additional single pre-treatment with one dose of the study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours. The surgical sample will be used for PK and PD analysis to determine the drug exposure and biological effect of the study drug in the tumor. More importantly, we plan to longitudinally evaluate Participant Reported Outcomes (PRO)s measures using self-reported symptom severity and interference with daily activities using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) or the M.D. Anderson Symptom Inventory-Spine Module (MDASI-SP) instrument. This will evaluate the symptom burdens and quality of life while patients receiving the treatment for tumor control. Lastly, the pharmacogenetic (PG) features of participants receiving ZOT will be determined and correlate with treatment response and toxicities. The results of this Phase 1 study have been completed and published.