Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis

神经肿瘤学中最大的两个挑战是胶质母细胞瘤的治疗和原发性脑肿瘤的治疗 黑色素瘤脑转移。两者都可以用放射和替莫唑胺治疗，但充其量这只是 延缓这些癌症的进展。基底膜和黑色素瘤都有显著的遗传特征 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个新的信号中枢，二酰甘油激酶α(DGKα)。我们之前的研究是关于 MicroRNA对肾小管上皮细胞的细胞毒性使我们发现它对Dgkα的敲除是其细胞毒性的主要驱动因素。 这表明了靶向该激酶的潜在效用。DGKα及其产物磷脂酸已经被 在许多具有致癌作用的信号通路中被发现是重要的，进一步支持DGKα的潜力 作为一个目标。我们最近报道了DGKα的敲除和小分子抑制导致细胞凋亡 无论是在体外还是在小鼠模型中，GBM和黑色素瘤细胞系的死亡。这些研究还表明 体内抗血管生成作用及mTOR和HIF-1α作为DGKα效应介导物的重要性 癌症。自从我们发表报告以来，我们发现一种被遗弃的药物在之前的 非癌症适应症瑞坦色林的临床试验是一种新型的DGKα抑制剂。重要的是，最近的报道 提示DGKα抑制剂具有打破T细胞无能和促进癌症免疫治疗的潜力。我们 因此，假设Ritanserin和其他新型DGKα抑制剂将对基底膜和 黑色素瘤脑转移，无论是作为单一药物还是与免疫疗法联合使用。在目标1中 在这项提议中，我们将测试可能的新型DGKα抑制剂对基底膜和黑色素瘤细胞表型的影响。 这些化合物是否影响DGK家族的其他成员，并评估可能的耐药机制。 目的2将研究瑞坦色林和其他新型DGKα抑制剂是否安全有效地治疗基底膜和 小鼠黑色素瘤异种移植模型。在目标3中，我们将在无记忆能力的小鼠中确定这些 DGKα抑制剂可增强局部免疫反应，并与免疫治疗具有协同作用。成功 拟议研究的完成将有助于阐明dgkα在基底膜中的生物学和治疗靶向性。 以及黑色素瘤脑转移，有可能迅速转化为临床试验。这一策略可能会 广泛适用于癌症，通过对癌细胞的直接细胞毒性、抗血管生成作用和增强 一系列前景看好的新免疫疗法。

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.