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

项目4：项目总结 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之一。病人 目前诊断为胶质母细胞瘤(GBM)的患者预后极差。中位存活率约为8-10 即使在手术切除和烷化化疗的标准护理方案之后(通常 替莫唑胺或TMZ)和放射治疗。这是因为，在几乎所有的患者中，肿瘤在治疗后复发。 因为GBM细胞可能会对治疗产生抵抗力。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 癌症的根源在于它的细胞分裂不受控制。由于癌细胞比正常细胞分裂更快，它们需要 更多的嘌呤，DNA和RNA的组成部分。嘌呤可以由氨基酸和其他 小分子通过从头生物合成途径或从微环境中循环通过 打捞路径。癌细胞使用从头生物合成途径，而中枢神经系统 通常更多地依赖于打捞途径。我们已经确定Arl13b是一种新的嘌呤调节剂 初步分析了化疗过程中的生物合成途径。Arl13b，ADP-核糖基化的成员 负责纤毛维持的类因子家族蛋白，直接与一磷酸肌苷相互作用 脱氢酶2(IMPDH2)，嘌呤生物合成的限速酶。我们最初的研究被推翻了 Arl13b抑制TMZ作用后GBM细胞对从头通路的利用 抢救生物合成途径。TMZ的治疗效果在体外和体内也得到了提高。 在Arl13b基因被击倒之后。因此，我们建议Arl13b-IMPDH2调节开关从 新嘌呤生物合成途径的挽救途径是GBM细胞适应烷化的必需途径。 以化疗为基础。在此基础上，我们假设GBM的治疗性转变涉及相互作用。 纤毛蛋白Arl13b与嘌呤生物合成限速酶IMPDH2的关系 (MMF)是FDA批准的用于器官移植的药物，它抑制IMPDH2的活性并允许增加 TMZ的治疗效果及延长患者来源异种移植(PDX)模型的存活时间 多个GBM亚型。这为克服GBM的化疗耐药提供了一个临床可翻译的机会。 在这项提案中，我们将进行MMF与标准化疗相结合的1/1b期临床试验 新诊断的GBM的放射治疗。主要目的是评估这种新型组合的安全性 和毒性，并确定最大耐受量(MTD)。探索性次要终端包括 无进展和总体生存。此外，我们打算研究霉酚酸，一种直接的 MMF的代谢物，可作为此类治疗的生物标记物。

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.