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

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。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，即使在手术切除、烷化化疗(通常是替莫唑胺或TMZ)和放射治疗的标准护理方案之后也是如此。这是因为，在几乎所有的患者中，由于GBM细胞可能对治疗产生抵抗力，肿瘤在治疗后会复发。我们实验室的目标是开发一种治疗基底膜的方法，以降低复发率并改善患者的预后。癌症的一个显著特征是细胞分裂不受控制。由于癌细胞比正常细胞分裂得更快，它们需要更多的嘌呤，这是DNA和RNA的组成部分。嘌呤要么由氨基酸和其他小分子通过从头合成途径合成，要么通过回收途径从微环境中循环。癌细胞通常使用新生物合成途径，而中枢神经系统通常更依赖挽救途径。通过初步分析，我们已经确定Arl13b是化疗过程中嘌呤生物合成途径的一个新的调节因子。Arl13b是ADP-核糖化因子样蛋白家族中负责纤毛维持的成员，它直接与嘌呤生物合成的限速酶--肌苷单磷酸脱氢酶2(IMPDH2)相互作用。我们的初步研究抑制了TMZ治疗后GBM细胞对从头途径的利用，而增加了对补救生物合成途径的利用。在体外和体内，在Arl13b基因敲除后，TMZ的治疗效果也得到了提高。因此，我们认为，Arl13b-IMPDH2调控的从挽救途径到从头合成嘌呤生物合成途径的转换是GBM细胞适应烷化化疗所必需的。基于此，我们假设GBM的治疗性转化涉及纤毛蛋白Arl13b和限速嘌呤生物合成酶IMPDH2霉酚酸酯(MMF)之间的相互作用，MMF是FDA批准的用于器官移植的药物，它抑制IMPDH2的活性，允许提高TMZ的治疗效果，并延长患者来源的异种移植(PDX)模型跨多种GBM亚型的存活。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，我们开始对新诊断的GBM进行MMF联合标准化疗和放射治疗的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，一种MMF的直接代谢物，可以作为此类治疗的生物标记物。

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.