Abstract
Simple SummaryGlioblastoma is the most common and aggressive brain cancer, and there is a desperate need for new therapeutic strategies for this incurable cancer. Inhibition of Diacylglycerol kinase α provides novel direct mechanisms against glioblastoma cells, but also offers the potential to simultaneously boost immune cell activities against glioblastoma. This review provides an updated summary of the promising potential of Diacylglycerol kinase α inhibition against glioblastoma, with potential implications for other cancers as well.Diacylglycerol kinase α (DGKα) inhibition may be particularly relevant for the treatment of glioblastoma (GBM), a relatively common brain malignancy incurable with current therapies. Prior reports have shown that DGKα inhibition has multiple direct activities against GBM cells, including suppressing the oncogenic pathways mTOR and HIF-1α. It also inhibits pathways associated with the normally treatment-resistant mesenchymal phenotype, yielding preferential activity against mesenchymal GBM; this suggests possible utility in combining DGKα inhibition with radiation and other therapies for which the mesenchymal phenotype promotes resistance. The potential for DGKα inhibition to block or reverse T cell anergy also suggests the potential of DGKα inhibition to boost immunotherapy against GBM, which is generally considered an immunologically “cold” tumor. A recent report indicates that DGKα deficiency increases responsiveness of macrophages, indicating that DGKα inhibition could also have the potential to boost macrophage and microglia activity against GBM—which could be a particularly promising approach given the heavy infiltration of these cells in GBM. DGKα inhibition may therefore offer a promising multi-pronged attack on GBM, with multiple direct anti-GBM activities and also the ability to boost both adaptive and innate immune responses against GBM. However, both the direct and indirect benefits of DGKα inhibition for GBM will likely require combinations with other therapies to achieve meaningful efficacy. Furthermore, GBM offers other challenges for the application of DGKα inhibitors, including decreased accessibility from the blood-brain barrier (BBB). The ideal DGKα inhibitor for GBM will combine potency, specificity, and BBB penetrability. No existing inhibitor is known to meet all these criteria, but the strong potential of DGKα inhibition against this lethal brain cancer should help drive development and testing of agents to bring this promising strategy to the clinic for patients with GBM.
Highlights
Diacylglycerol kinase alpha (DGKα) is one of ten DGK family members that convert diacylglycerols (DAGs) to phosphatidic acids (PAs)
Diacylglycerol kinase α (DGKα) is increasingly associated with numerous biologic processes, and its inhibition may be promising for many pathologies and diseases
DGKα inhibition may be relevant for the treatment of glioblastoma (GBM), the most common brain malignancy and one which is incurable with current therapies
Summary
Diacylglycerol kinase alpha (DGKα) is one of ten DGK family members that convert diacylglycerols (DAGs) to phosphatidic acids (PAs). Both DAG and PA strongly regulate numerous biologic processes. DGKα is increasingly associated with numerous biologic processes, and its inhibition may be promising for many pathologies and diseases. This is certainly true for cancer, in which DGKα inhibition may have direct action against cancer cells and stimulate the immune system to better attack cancers. This review will discuss how the potential benefits of DGKα inhibition may make it a good fit for the clinical challenges of treating GBM as part of combination regimens
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