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 ? (DGK?). Our prior studies of a microRNA cytotoxic to GBM cells led us to identify its knockdown of DGK? as a major driver of its cytotoxicity, indicating the potential utility of targeting this kinase. DGK? ad its product phosphatidic acid had already been found important in numerous signaling pathways with oncogenic roles, further supporting the potential of DGK? as a target. We recently reported that knockdown and small-molecule inhibition of DGK? 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-1? as mediators of DGK? 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 DGK? inhibitor. Importanty, recent reports suggest that DGK? inhibitors have the potential to break T cell anergy and boost cancer immunotherapies. We therefore hypothesize that ritanserin and other novel DGK? 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 DGK? 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 DGK? inhibitors are safe and effective in GBM and melanoma mouse xenograft models.
In Aim 3, we will determine in immnocompetent mice whether these DGK? 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 DGK? in GBM and melanoma brain metastases, with the potential for rapid translation to clinical trials. This strategy may have broad applicabiity in cancer, acting via direct cytotoxicity to cancer cells, antiangiogenic effects, and enhancing a host of promising new immunotherapies.

Public Health Relevance

Two of the greatest challenges in neuro-oncology are treating glioblastoma brain tumors and melanoma metastatic to the brain. Glioblastoma is the most common and lethal brain tumor, highly resistant to standard treatments. This project investigates novel inhibitors of diacylglycerol kinase alpha (DGK?) as treatments for glioblastoma and for melanoma brain metastases. These compounds are being assessed as single agents and for their potential to boost cancer immunotherapy, with likely implications for treating other cancers as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA189524-04S1
Application #
9571638
Study Section
Program Officer
Schwartz, Elena Ivan
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Virginia
Department
Neurology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Olmez, Inan; Love, Shawn; Xiao, Aizhen et al. (2018) Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha. Neuro Oncol 20:192-202
Olmez, Inan; Zhang, Ying; Manigat, Laryssa et al. (2018) Combined c-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors in Glioblastoma. Cancer Res 78:4360-4369
McCloud, Rebecca L; Franks, Caroline E; Campbell, Sean T et al. (2018) Deconstructing Lipid Kinase Inhibitors by Chemical Proteomics. Biochemistry 57:231-236
Li, Ming; Xiao, Aizhen; Floyd, Desiree et al. (2017) CDK4/6 inhibition is more active against the glioblastoma proneural subtype. Oncotarget 8:55319-55331
Franks, Caroline E; Campbell, Sean T; Purow, Benjamin W et al. (2017) The Ligand Binding Landscape of Diacylglycerol Kinases. Cell Chem Biol 24:870-880.e5
Boroda, Salome; Niccum, Maria; Raje, Vidisha et al. (2017) Dual activities of ritanserin and R59022 as DGK? inhibitors and serotonin receptor antagonists. Biochem Pharmacol 123:29-39
Olmez, Inan; Brenneman, Breanna; Xiao, Aizhen et al. (2017) Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms. Clin Cancer Res 23:6958-6968
Purow, Benjamin (2015) Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer. Clin Cancer Res 21:5008-12