Arginine deprivation using ADI-PEG20 leads to regression of an ASS-ve intracranial GBM tumour in mice and potentiates gamma irradiation of ASS+ve GBM in vitro.
Presented at AACR 2015
Abaitua F., Przystal JM., Hajitou A., O’Neill K and Syed N.
Patients with Gliobastoma Multiforme (GBM) have an extremely poor overall survival rate. Novel molecular targeted therapies have failed to provide further improvements in these rates and as such the standard of care for GBM patients remains unchanged, consisting of radical surgery followed by chemo and radiotherapy. In light of this, novel therapeutic approaches have to be tested in combination with current protocols for their efficacy. We have previously demonstrated the metabolic dependency of ~30% of de novo GBM to extracellular arginine. Using ADI-PEG20 to deplete arginine, we showed a marked reduction in the proliferation of primary GBM explants that exhibited methylation in their ASS1 gene, the rate-limiting enzyme in the arginine biosynthetic pathway.
We have validated these findings in an animal model where we have demonstrated that ADI-PEG20 treatment induces a profound delay in the growth of ASS1-ve intracranial human GBM tumours in mice. In cell culture models, we show that ADI-PEG20 has comparable cell growth inhibition efficiencies as conventional chemotherapies namely temozolomide, lomustine and chloroquine. Moreover, these agents exhibited inhibitory effects on proliferation in hypoxic conditions (1% O2) representing activity in a more physiological environment. Importantly, combination with ADI-PEG20 did not reduce efficiency of the conventional drugs. Although we did not observe any synergistic effects of ADI-PEG20 and these chemotherapeutic agents, synergy was observed with irradiation. Here, we showed the ADI-PEG20 radio-sensitized GBM cell lines to photon irradiation regardless of their ASS1 methylation status: In clonogenic assays, there was 50% enhanced decrease in colony formation with pre-treatment of ADI-PEG20 and subsequent photon irradiation when compared to irradiation alone.
These results suggest arginine deprivation therapy as a novel therapeutic strategy for ASS-ve GBM. Moreover, we show that when combined with irradiation, ADI-PEG20 can be used to treat GBM irrespective of their ASS1 status.