Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis

点击翻译按钮获取中文摘要

Two of the greatest challenges in neuro-oncology are the treatment of glioblastoma primary brain tumors and melanoma brain metastases. Both may be treated with radiation and temozolomide, but at best this merely delays the progression of these cancers. Both GBM and melanoma are marked by substantial genetic heterogeneity and by the ability to adapt to targeted therapies. This Project attempts to address both problems through targeting a novel signaling hub in cancer, diacylglycerol kinase α (DGKα). Our prior studies of a microRNA cytotoxic to GBM cells led us to identify its knockdown of DGKα as a major driver of its cytotoxicity, indicating the potential utility of targeting this kinase. DGKα and its product phosphatidic acid had already been found important in numerous signaling pathways with oncogenic roles, further supporting the potential of DGKα as a target. We recently reported that knockdown and small-molecule inhibition of DGKα causes apoptotic cell death in GBM and melanoma lines, both in vitro and in mouse models. These studies also indicated antiangiogenic effects in vivo and the importance of mTOR and HIF-1α as mediators of DGKα effects in cancer. Since our published report, we have discovered that an abandoned medication found safe in prior clinical trials for a non-cancer indication, ritanserin, is a novel DGKα inhibitor. Importantly, recent reports suggest that DGKα inhibitors have the potential to break T cell anergy and boost cancer immunotherapies. We therefore hypothesize that ritanserin and other novel DGKα inhibitors will be highly effective against GBM and brain metastases from melanoma, both as single agents and in combination with immunotherapy. In Aim 1 of this proposal, we will test the effects of putative novel DGKα inhibitors on GBM and melanoma cell phenotype, whether these compounds affect other DGK family members, and assess possible resistance mechanisms. Aim 2 will investigate whether ritanserin and other novel DGKα inhibitors are safe and effective in GBM and melanoma mouse xenograft models. In Aim 3, we will determine in immnocompetent mice whether these DGKα inhibitors increase the local immune response and are synergistic with immunotherapy. Successful completion of the proposed studies will shed light on the biology and therapeutic targeting of DGKα in GBM and melanoma brain metastases, with the potential for rapid translation to clinical trials. This strategy may have broad applicability in cancer, acting via direct cytotoxicity to cancer cells, antiangiogenic effects, and enhancing a host of promising new immunotherapies.