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。目前被诊断患有胶质母细胞瘤（GBM）的患者预后很差。即使采用手术切除后进行烷化化疗（通常为替莫唑胺或 TMZ）和放疗的标准治疗方案，中位生存期约为 8-10 个月。这是因为，几乎所有患者在治疗后肿瘤都会复发，因为 GBM 细胞会对治疗产生耐药性。我们实验室的目标是开发一种 GBM 治疗方法，以降低复发率并改善患者的预后。癌症的显着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，因此它们需要更多的嘌呤（DNA 和 RNA 的组成部分）。嘌呤要么通过从头生物合成途径由氨基酸和其他小分子合成，要么通过回收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依赖于挽救途径。通过初步分析，我们发现 ARL13B 是化疗期间嘌呤生物合成途径的新型调节剂。 ARL13B 是负责维持纤毛的 ADP 核糖基化因子样家族蛋白的成员，可直接与嘌呤生物合成限速酶肌苷单磷酸脱氢酶 2 (IMPDH2) 相互作用。我们的初步研究显示，在 TMZ 治疗后，敲低 ARL13B 会抑制 GBM 细胞对从头途径的利用，并增加对补救生物合成途径的利用。 ARL13B 敲低后，TMZ 治疗的体外和体内有效性也得到提高。因此，我们提出，ARL13B-IMPDH2 调节的从挽救途径到从头嘌呤生物合成途径的转换对于 GBM 细胞适应基于烷化的化疗是必要的。基于此，我们假设 GBM 的治疗转化涉及纤毛蛋白 ARL13B 和限速嘌呤生物合成酶 IMPDH2 之间的相互作用。吗替麦考酚酯 (MMF) 是 FDA 批准用于器官移植的药物，可抑制 IMPDH2 活性并允许增加TMZ 的治疗功效并延长了多个 GBM 亚型的患者来源的异种移植 (PDX) 模型的生存期。这为克服 GBM 的化疗耐药性提供了临床可转化的机会。在该提案中，我们计划对新诊断的 GBM 进行 MMF 联合标准化疗和放疗的 1/1b 期临床试验。主要目标是评估这种新型组合的安全性和毒性并确定最大耐受剂量（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，它是 MMF 的直接代谢产物，可以作为此类疗法的生物标志物。