PM-02 * DIACYLGLYCEROL KINASE ALPHA INHIBITION PROLONGS SURVIVAL OF MICE WITH PRIMARY AND METASTATIC BRAIN TUMORS

Abstract

Diacylglycerol kinases (DGKs) are a family of highly conserved enzymes that are promiscuously responsive to growth factors and other mitogenic signaling cascades. DGKs are activated by binding of Ca2+ and phosphoserine, and catalyze conversion of diacylglycerol (DAG) to phosphatidic acid (PA). PA has multiple effects on downstream cellular signaling, while activated DGKs can associate with scaffolding proteins, or undergo degradation or translocation to the nucleus through atypical localization signals and thereby promote cell division and survival. A repurposed small-molecule inhibitor of DGKα activity is shown here to antagonize tumor growth in xenografts of primary and metastatic brain tumors and syngeneic mouse tumor grafts. Based on recent prior research and in this work in xenograft models, DGKα inhibition may arrest or kill tumors through cancer addiction to DGKα activity. Here, in syngeneic tumor models of primary and metastatic brain tumors, an additional anti-tumor effect of DGKα inhibition via up-regulation of normal immune function is possibly present. This work uses two syngeneic in vivo tumor models to compare DGKα inhibition with the monoclonal antibody immunotherapy anti-CTLA-4, and also tests the effect of combination of the two treatments on survival, tumor size, and immunologic activity. The anti-tumor activity of the DGKα inhibitor and the contribution of other DGK family members is shown using cell-based toxicity and flow cytometry assays. Direct interaction between the inhibitor and DGKα is shown with biochemical reconstitution of inhibitor-enzyme interactions These early results suggest that DGKα inhibition may be a promising strategy for patients with glioblastoma and melanoma brain metastasis.