A Phase 1 Adaptive Dose Escalation Study of Mycophenolate Mofetil in Combination with Temozolomide for Patients with Newly Diagnosed Glioblastoma

项目4：项目概要 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。患者 目前诊断为胶质母细胞瘤（GBM）的患者预后极差。中位生存期在8-10岁左右 即使在手术切除后进行烷化剂化疗的标准护理方案（通常 替莫唑胺或TMZ）和放疗。这是因为，几乎所有患者的肿瘤在治疗后都会复发 因为GBM细胞会对治疗产生抗性。我们实验室的目标是开发一种治疗GBM的方法， 将降低复发率，改善患者预后。其中一个显著的特点是 癌症的关键在于它不受控制的细胞分裂。由于癌细胞比正常细胞分裂得更快， 更多的嘌呤，DNA和RNA的基本组成部分。嘌呤是由氨基酸和其他氨基酸合成的。 小分子通过从头生物合成途径或从微环境中回收， 抢救路径。癌细胞使用从头生物合成途径，而中枢神经系统 通常更依赖于抢救途径。我们已经确定ARL 13 B是一种新的嘌呤调节因子， 生物合成途径进行初步分析。ARL 13 B是ADP核糖基化的一员， 负责纤毛维持的因子样家族蛋白，直接与肌苷一磷酸相互作用 脱氢酶2（IMPDH 2），嘌呤生物合成的限速酶。我们最初的研究 ARL 13 B抑制TMZ处理后GBM细胞对从头途径的利用，并增加TMZ处理后GBM细胞对 补救生物合成途径。TMZ治疗的有效性在体外和体内也有所提高 在ARL 13 B敲除之后。因此，我们建议将ARL 13 B-IMPDH 2调节开关从 从补救途径到从头嘌呤生物合成途径是GBM细胞适应烷基化所必需的。 基础化疗。基于此，我们假设GBM的治疗转化涉及相互作用 纤毛蛋白ARL 13 B和限速嘌呤生物合成酶IMPDH 2之间的关系 (MMF)FDA批准的用于器官移植的药物，抑制IMPDH 2活性， TMZ的治疗功效和延长患者来源的异种移植物（PDX）模型的存活， 多种GBM亚型。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1/1b期临床试验， 对新诊断的GBM进行放疗。主要目的是评价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，我们打算调查麦考酚酸，立即 在一些实施方案中，本发明提供了可以用作这种治疗的生物标志物的MMF的代谢物。

PROJECT 4: PROJECT SUMMARY Glioblastoma (GBM), a grade IV tumor, is one of the most aggressive and infiltrative brain cancer forms. Patients 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 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 patient-derived 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.