Discovering novel therapies for glioma patients

发现神经胶质瘤患者的新疗法

• 批准号: 10926356
• 负责人: Jing Wu
• 金额: $ 66.33万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926356
• 关键词: Apoptosis; Apoptotic; Biological; Biopsy; Brain Neoplasms; CDK9 Protein Kinase; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; DNA Polymerase II; Databases; Disease Resistance; Doctor of Medicine; Dose; Drug Exposure; Equipment and supply inventories; Excision; Genetic Transcription; Glioma; Grant; Hour; In Vitro; Isocitrate Dehydrogenase; Malignant Glioma; Malignant neoplasm of brain; Modeling; Molecular; Mus; Mutation; Operative Surgical Procedures; Orphan Drugs; Outcome; Outcome Measure; Participant; Pathway interactions; Patient Outcomes Assessments; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phase I/II Clinical Trial; Prognostic Factor; Progression-Free Survivals; Proteins; Publishing; Quality of life; RNA; Recommendation; Recurrence; Reporting; Safety; Sampling; Severities; Survival Rate; Symptoms; Testing; Therapeutic Effect; Toxic effect; Transcription Process; Treatment-related toxicity; Tumor Biology; Vertebral column; Work; World Health Organization; antitumor effect; cell type; clinical prognostic; clinical trial analysis; cohort; design; disease heterogeneity; improved; in vivo Model; inhibitor; instrument; mitochondrial dysfunction; mouse model; mutant; novel therapeutics; phase 1 study; phase I trial; phase II trial; pre-clinical; preclinical study; preservation; primary endpoint; resistance mechanism; response; systemic toxicity; targeted treatment; therapy development; therapy resistant; treatment response; tumor

Based on our previous preclinical and clinical works in high-grade malignant gliomas, FDA granted the orphan drug designation for ZTR in malignant gliomas treatment. Based on the observations from the previous clinical study, we continued to investigate the selective effect of ZTR in a subset of gliomas. This ongoing project includes both preclinical and clinical studies of ZTR in IDH-mutant gliomas. In the preclinical studies, we tested the responses to ZTR in both IDH mutant and wildtype glioma models. We demonstrated the increased sensitivity to ZTR 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 ZTR 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 ZTR-treated IDH-mutant gliomas but not in IDH wildtype tumors. A significant survival benefit of single-agent ZTR 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 ZTR due to its unique tumor biology. Single-agent ZTR 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 ZTR 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 ZTR will be determined and correlate with treatment response and toxicities. The results of this Phase 1 study have been completed and published.

基于我们之前在高级别恶性胶质瘤方面的临床前和临床工作，FDA授予ZTR用于治疗恶性胶质瘤的孤儿药称号。基于之前临床研究的观察结果，我们继续研究ZTR在胶质瘤亚型中的选择性作用。这个正在进行的项目包括 ZTR 在 IDH 突变神经胶质瘤中的临床前和临床研究。在临床前研究中，我们测试了 IDH 突变型和野生型神经胶质瘤模型对 ZTR 的反应。我们证明了与 IDH 野生型肿瘤相比，IDH 突变型神经胶质瘤对 ZTR 的敏感性增加。在患者来源的 GSC 系以及具有和不具有 IDH 突变的同基因小鼠细胞中，IDH 突变细胞的 IC50 低于 IDH 野生型神经胶质瘤细胞。较低剂量的 ZTR 能够通过抑制突变细胞中的细胞周期蛋白依赖性激酶 9 (CDK9) 和 RNAPOL II 来抑制转录，但在野生型细胞中则不然。细胞凋亡、线粒体功能障碍和 ATP 减少也见于低剂量 ZTR 治疗的 IDH 突变神经胶质瘤，但未见于 IDH 野生型肿瘤。在 IDH 突变小鼠模型中观察到单药 ZTR 具有显着的生存益处，但在野生型神经胶质瘤中却没有。根据临床前研究结果，我们假设 IDH 突变神经胶质瘤由于其独特的肿瘤生物学而对 ZTR 的敏感性增加。 IDH 突变神经胶质瘤患者的单药 ZTR 将改善临床结果，包括生存获益和更少的毒性。为了在临床试验中检验这一假设，我设计了一项针对 IDH 突变神经胶质瘤患者的临床试验。标题为“Zotiraciclib 用于治疗异柠檬酸脱氢酶 1 或 2（IDH1 或 IDH2）突变的复发性高级别胶质瘤的 I/II 期研究”。在第一阶段部分，主要目标是估计 ZOT 的推荐第二阶段剂量 (RP2D)。在第二阶段，主要目标是确定接受 ZTR 治疗的复发性神经胶质瘤、IDH1/2 突变、世界卫生组织 (WHO) 3 级患者的 12 个月无进展生存期 (PFS)，并与已建立的与肿瘤分子特征和临床预后因素相匹配的脑肿瘤数据库进行比较。在第二阶段部分，我们建立了一个手术队列。手术队列的参与者将在第 0 周期第 1 天的 RP2D 接受额外的单次预治疗，使用一剂研究药物，然后在 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效应。更重要的是，我们计划使用 M.D. Anderson 症状清单-脑肿瘤 (MDASI-BT) 或 M.D. Anderson 症状清单-脊柱模块 (MDASI-SP) 仪器，使用自我报告的症状严重程度和对日常活动的干扰来纵向评估参与者报告结果 (PRO) 措施。这将评估患者接受肿瘤控制治疗时的症状负担和生活质量。最后，将确定接受 ZTR 的参与者的药物遗传学 (PG) 特征，并将其与治疗反应和毒性相关联。第一阶段研究的结果已经完成并发表。

项目成果

Exploring the prevalence and burden of sleep disturbance in primary brain tumor patients.

探讨原发性脑肿瘤患者睡眠障碍的患病率和负担。

• DOI: 10.1093/nop/npac049
• 发表时间: 2022
• 期刊: Neuro-oncology practice
• 影响因子: 2.7
• 作者: King,AmandaL;Shuboni-Mulligan,DorelaD;Vera,Elizabeth;Crandon,Sonja;Acquaye,AlvinaA;Boris,Lisa;Burton,Eric;Choi,Anna;Christ,Alexa;Grajkowska,Ewa;Jammula,Varna;Leeper,HeatherE;Lollo,Nicole;Penas-Prado,Marta;Reyes,Jennifer;T
• 通讯作者: T

Rethinking Immunotherapy in Meningiomas.

• DOI: 10.1093/neuonc/noab168
• 发表时间: 2021-07
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: M. Terabe;Jing Wu

Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas.

复发性高级星形胶质细胞瘤患者的唑吡迪布与替莫唑胺结合的I期研究。

• DOI: 10.1158/1078-0432.ccr-20-4730
• 发表时间: 2021-06-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Wu J;Yuan Y;Long Priel DA;Fink D;Peer CJ;Sissung TM;Su YT;Pang Y;Yu G;Butler MK;Mendoza TR;Vera E;Ahmad S;Bryla C;Lindsley M;Grajkowska E;Mentges K;Boris L;Antony R;Garren N;Siegel C;Lollo N;Cordova C;Aboud O;Theeler BJ;Burton EM;Penas-Prado M;Leeper H;Gonzales J;Armstrong TS;Calvo KR;Figg WD;Kuhns DB;Gallin JI;Gilbert MR
• 通讯作者: Gilbert MR

Feasibility of a virtual reality intervention targeting distress and anxiety symptoms in patients with primary brain tumors: Interim analysis of a phase 2 clinical trial.

• DOI: 10.1007/s11060-023-04271-0
• 发表时间: 2023-03
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: King, Amanda L.;Roche, Kayla N.;Leeper, Heather E.;Vera, Elizabeth;Mendoza, Tito;Mentges, Kelly;Acquaye-Mallory, Alvina A.;Adegbesan, Kendra A.;Boris, Lisa;Burton, Eric;Choi, Anna;Grajkowska, Ewa;Kunst, Tricia;Levine, Jason;Lollo, Nicole;Miller, Hope;Panzer, Marissa;Penas-Prado, Marta;Pillai, Valentina;Polskin, Lily;Reyes, Jennifer;Sahebjam, Solmaz;Stockdill, Macy L.;Theeler, Brett J.;Wu, Jing;Gilbert, Mark R.;Armstrong, Terri S.
• 通讯作者: Armstrong, Terri S.