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IV级肿瘤，是最具侵略性和浸润性的脑癌形式之一。目前被诊断为胶质母细胞瘤（GBM）的患者的预后糟糕。即使在手术切除的标准护理方案随后进行烷基化疗（通常是替莫唑胺或TMZ）和放射疗法之后，中位生存期也约为8-10个月。这是因为在几乎所有患者中，肿瘤在治疗后都会出现，因为GBM细胞可以对治疗具有抵抗力。我们的实验室的目标是为GBM开发一种治疗方法，以降低复发率并改善患者的预后。癌症的区别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更快地分裂，因此需要更多的嘌呤，即DNA和RNA的组成部分。嘌呤要么是通过从头生物合成途径从氨基酸和其他小分子合成的，要么通过打捞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取决于打捞途径。通过初步分析，我们已经将ARL13B确定为化学疗法期间嘌呤生物合成途径的新调节剂。 ARL13B是ADP-核糖基化因子样蛋白蛋白质的成员，对纤毛维持负有责任，它直接与肌苷一磷酸脱氢酶2（IMPDH2）直接相互作用，这是速率限制酶的嘌呤生物合成。我们的最初研究敲除ARL13B的研究抑制了GBM细胞在TMZ处理后对从头途径的利用，并增加了保证生物合成途径的利用。 ARL13B敲低后，TMZ处理的有效性也升高了体外和体内。因此，我们提出，ARL13B-IMPDH2从挽救途径转向从头嘌呤生物合成途径是GBM细胞对基于烷基化化学疗法的适应性所必需的。基于这一点，我们假设GBM中的治疗转化涉及睫状蛋白ARL13B与限制速率的嘌呤生物合成酶Impdh2霉菌酸酯Mofetil（MMF），这是FDA批准的药物，在机构转移的设置中，可以抑制这种情况，并限制了IMPD HED的限制。多种GBM亚型的患者异种移植（PDX）模型的存活。这为克服GBM的化学耐药性提供了一个可翻译的机会。在此提案中，我们开始对新诊断的GBM进行MMF的1/1B临床试验以及标准化学疗法和放射疗法。主要目标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和整体生存。此外，我们打算研究霉酚酸，这是立即的MMF代谢产物，可以用作这种治疗的生物标志物。