Role of purine metabolism in chemoresistance

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PROJECT SUMMARY Glioblastoma (GBM), a grade IV tumor, is one of the most aggressive and infiltrative forms of brain cancer. Patients that are currently diagnosed with Glioblastoma (GBM) have a very poor prognosis. 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 cell can become resistant to therapy. Our goal is to develop a treatment for GBM that will reduce recurrence rate and thereby 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. (The purine biosynthesis pathway has previously been implicated in resistance to chemotherapy). 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 nerves system usually rely more on the salvage pathway. Through initial analysis, we have identified ARL13B as a novel regulator of the purine biosynthesis pathway during chemotherapy. 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. In 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 hypothesize 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. The goal of this study is to further investigate this hypothesis through the following aims: 1) examine the role of ARL13B in regulating purine metabolism; 2) elucidate the role of purine metabolism in promoting resistance to TMZ; 3) modulate the purine biosynthesis pathway to overcome the resistance against the alkylating-based chemotherapy. Overall, we hope to gain novel insight into the role of purine metabolism in GBM in the context of therapeutic resistance with the end goal of developing a translational therapy to prevent GBM recurrence.!