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

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.