Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis

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的治疗， 黑素瘤脑转移两者都可以用放疗和替莫唑胺治疗，但最好的情况是， 延缓这些癌症的发展。GBM和黑色素瘤都有大量的遗传标记， 异质性和适应靶向治疗的能力。本项目试图解决这两个问题 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α（DGKα）。我们之前的研究 对GBM细胞具有细胞毒性的microRNA使我们确定其对DGKα的敲低是其细胞毒性的主要驱动因素， 表明靶向该激酶的潜在效用。DGKα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很重要，进一步支持DGKα的潜力 作为目标。我们最近报道了DGKα的敲低和小分子抑制可导致细胞凋亡， 在体外和小鼠模型中，GBM和黑色素瘤细胞系的死亡。这些研究还表明， 体内的抗血管生成作用以及mTOR和HIF-1α作为DGKα作用的介导物在 癌自从我们发表报告以来，我们发现一种废弃的药物在以前的研究中发现是安全的。 非癌症适应症的临床试验，利坦色林是一种新型DGKα抑制剂。重要的是，最近的报告 这表明DGKα抑制剂具有打破T细胞无反应性和增强癌症免疫治疗的潜力。我们 因此，假设利坦色林和其他新型DGKα抑制剂对GBM非常有效， 黑色素瘤的脑转移，作为单一药剂和与免疫疗法组合。目标1， 在这项提议中，我们将测试推定的新型DGKα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DGKα抑制剂在GBM中是否安全有效， 黑素瘤小鼠异种移植模型。在目标3中，我们将在免疫活性小鼠中确定这些细胞是否 DGKα抑制剂可增强局部免疫应答，并与免疫治疗具有协同作用。成功 这些研究的完成将有助于阐明DGKα在GBM中的生物学和治疗靶点 和黑色素瘤脑转移，具有快速转化为临床试验的潜力。这一战略可能 在癌症中的广泛适用性，通过对癌细胞的直接细胞毒性起作用，抗血管生成作用，并增强 一系列有前途的新免疫疗法

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.