Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis

描述（由申请人提供）：神经肿瘤学的两个最大挑战是原发性脑肿瘤胶质母细胞瘤和脑转移瘤的治疗。两者都可以用放疗和替莫唑胺治疗，但这充其量只能延缓这些癌症的进展。GBM和黑色素瘤都具有显著的遗传异质性和适应靶向治疗的能力。该项目试图通过针对癌症中的一个新的信号中枢，二酰基甘油激酶（DGK）来解决这两个问题。我们之前对一种对GBM细胞具有细胞毒性的microRNA的研究使我们确定其对DGK的敲低是其细胞毒性的主要驱动因素，这表明靶向这种激酶的潜在效用。DGK -及其产物磷脂酸已被发现在许多具有致癌作用的信号通路中起重要作用，进一步支持DGK -作为靶点的潜力。我们最近报道，在体外和小鼠模型中，DGK的敲低和小分子抑制导致GBM和黑色素瘤细胞系的凋亡细胞死亡。这些研究还表明了体内抗血管生成作用以及mTOR和HIF-1作为DGK -在癌症中的作用介质的重要性。自我们发表报告以来，我们发现在先前的非癌症适应症临床试验中发现一种被遗弃的药物利坦色林是一种新型DGK抑制剂。重要的是，最近的报道表明，DGK抑制剂具有破坏T细胞能量和促进癌症免疫治疗的潜力。因此，我们假设利坦色林和其他新型DGK抑制剂对GBM和黑色素瘤脑转移瘤非常有效，无论是单独使用还是与免疫疗法联合使用。在本提案的目的1中，我们将测试假定的新型DGK抑制剂对GBM和黑色素瘤细胞表型的影响，这些化合物是否影响其他DGK家族成员，并评估可能的耐药机制。目的2将研究利坦色林和其他新型DGK抑制剂在GBM和黑色素瘤小鼠异种移植模型中是否安全有效。在Aim 3中，我们将在免疫能力小鼠中确定这些DGK抑制剂是否增加局部免疫反应并与免疫治疗协同作用。这些研究的成功完成将揭示DGK在GBM和黑色素瘤脑转移中的生物学和治疗靶向，并有可能快速转化为临床试验。这种策略可能在癌症中具有广泛的适用性，通过对癌细胞的直接细胞毒性作用，抗血管生成作用以及增强一系列有前途的新免疫疗法。

DESCRIPTION (provided by applicant): 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.