phase 1 adaptive dose-escalation study of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ) for patients with newly diagnosed glioblastoma

霉酚酸酯（MMF）联合替莫唑胺（TMZ）治疗新诊断胶质母细胞瘤患者的 1 期适应性剂量递增研究

• 批准号: 10478885
• 负责人: Atique U. Ahmed
• 金额: $ 28.95万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478885
• 关键词: phase; adaptive; dose; escalation; study

Glioblastoma (GBM), a grade IV tumor, is one of the most aggressive and infiltrative brain cancer forms. Patients that are currently diagnosed with Glioblastoma (GBM) have an abysmal prognosis. The median survival is around 8-10 months, even after the standard care protocol of surgical resection followed by alkylating chemotherapy (typically temozolomide or TMZ) and radiotherapy. This is because, in nearly all patients, the tumor recurs after treatment since GBM cells can become resistant to therapy. Our laboratory's goal is to develop a treatment for GBM that will reduce the recurrence rate and improve the prognosis for patients. One of the distinguishing characteristics of cancer is its uncontrolled cell division. Since cancer cells divide more rapidly than normal cells, they require more purines, the building blocks of DNA and RNA. Purines are either synthesized from amino acids and other small molecules through the de novo biosynthesis pathway or are recycled from the microenvironment through the salvage pathway. Cancer cells typically use the de novo biosynthesis pathway, whereas the central nervous system usually relies more on the salvage pathway. We have identified ARL13B as a novel regulator of the purine biosynthesis pathway during chemotherapy through initial analysis. ARL13B, a member of the ADP-ribosylation factor-like family protein accountable for cilia maintenance, directly interacts with inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme purine biosynthesis. Our initial studies knocking-down ARL13B inhibited GBM cells' utilization of the de novo pathway after TMZ treatment and increased utilization of the salvage biosynthesis pathway. The effectiveness of TMZ treatment was also elevated in vitro and in vivo following ARL13B knockdown. We, therefore, proposed that the ARL13B-IMPDH2 regulated switch from the salvage pathway to the de novo purine biosynthesis pathway is necessary for GBM cells' adaptation to alkylating-based chemotherapy. Based on this, we hypothesize that therapeutic transformation in GBM involves interaction between ciliary protein ARL13B and rate-limiting purine biosynthesis enzyme IMPDH2 Mycophenolate mofetil (MMF), an FDA-approved drug in the organ-transplant setting, inhibits IMPDH2 activity and allows for increased the therapeutic efficacy of TMZ and extended the survival of patientderived xenograft (PDX) models across multiple GBM subtypes. This provides a clinically translatable opportunity to overcome chemoresistance in GBM. In this proposal, we set to conduct a Phase 1/1b clinical trial of MMF combined with standard chemo- and radiotherapy for newly diagnosed GBM. The primary objectives are to evaluate this novel combination's safety and toxicity and establish the maximally tolerated dose (MTD). Exploratory secondary endpoints include progression-free and overall survival. Furthermore, we intend to investigate mycophenolic acid, an immediate metabolite of MMF that can serve as a biomarker for such therapy.

胶质母细胞瘤（GBM）是一种IV级肿瘤，是最具侵袭性和浸润性的脑癌形式之一。目前诊断为胶质母细胞瘤（GBM）的患者预后极差。中位生存期约为8-10个月，即使在标准治疗方案的手术切除术后，随后进行烷化剂化疗（通常为替莫唑胺或TMZ）和放疗。这是因为，在几乎所有患者中，肿瘤在治疗后复发，因为GBM细胞可以对治疗产生抗性。我们实验室的目标是开发一种治疗GBM的方法，以降低复发率并改善患者的预后。癌症的显著特征之一是其不受控制的细胞分裂。由于癌细胞比正常细胞分裂得更快，它们需要更多的嘌呤，DNA和RNA的构建模块。嘌呤可以通过从头生物合成途径由氨基酸和其他小分子合成，也可以通过补救途径从微环境中回收。癌细胞通常使用从头生物合成途径，而中枢神经系统通常更多地依赖于补救途径。通过初步分析，我们已经确定ARL 13 B是化疗期间嘌呤生物合成途径的一种新型调节剂。ARL 13 B是负责纤毛维持的ADP-核糖基化因子样家族蛋白的成员，直接与嘌呤生物合成的限速酶肌苷一磷酸脱氢酶2（IMPDH 2）相互作用。我们的初步研究敲低ARL 13 B抑制了TMZ处理后GBM细胞对从头途径的利用，并增加了补救生物合成途径的利用。TMZ治疗的有效性也在ARL 13 B敲低后在体外和体内升高。因此，我们提出ARL 13 B-IMPDH 2调节的从补救途径到从头嘌呤生物合成途径的转换对于GBM细胞适应基于烷基化的化疗是必需的。基于此，我们假设GBM中的治疗转化涉及纤毛蛋白ARL 13 B和限速嘌呤生物合成酶IMPDH 2霉酚酸酯（MMF）之间的相互作用，霉酚酸酯（MMF）是FDA批准的器官移植药物，可抑制IMPDH 2活性，提高TMZ的疗效，延长多种GBM亚型患者来源的异种移植（PDX）模型的生存期。这为克服GBM中的化学抗性提供了临床上可转化的机会。在这项提案中，我们将进行一项MMF联合标准化疗和放疗治疗新诊断GBM的1/1b期临床试验。主要目的是评估这种新型组合的安全性和毒性，并建立最大耐受剂量（MTD）。探索性次要终点包括无进展生存期和总生存期。此外，我们打算研究霉酚酸，霉酚酸的直接代谢产物，可以作为这种治疗的生物标志物。