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胶质母细胞瘤原发性脑肿瘤和黑色素瘤脑转移瘤的治疗。两者都可以用放疗和替莫唑胺治疗，但充其量只是延缓这些癌症的进展。GBM和黑色素瘤都以大量的遗传异质性和适应靶向治疗的能力为标志。该项目试图通过靶向癌症中的一种新型信号传导中心--二酰基甘油激酶（DGK）来解决这两个问题。我们先前对GBM细胞毒性microRNA的研究使我们确定其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。已经发现DGK及其产物磷脂酸在许多具有致癌作用的信号通路中很重要，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 β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效应介质在癌症中的重要性。自从我们发表报告以来，我们发现一种在先前的非癌症适应症临床试验中发现安全的废弃药物ritanserin是一种新型DGK抑制剂。重要的是，最近的报告表明，DGK抑制剂有可能打破T细胞无反应性和促进癌症免疫治疗。因此，我们假设利坦色林和其他新型DGK抑制剂将对GBM和黑色素瘤脑转移非常有效，无论是作为单一药物还是与免疫疗法联合使用。在本提案的目标1中，我们将测试推定的新型DGK β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。目标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。在目标3中，我们将在免疫活性小鼠中确定这些DGK抑制剂是否增加局部免疫反应，并与免疫治疗协同作用。拟议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作用，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、抗血管生成作用起作用，并增强许多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.