Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis

描述(由申请人提供)：神经肿瘤学中最大的两个挑战是胶质母细胞瘤、原发脑肿瘤和黑色素瘤脑转移的治疗。两者都可以用放射治疗和替莫唑胺治疗，但这充其量只是延缓了这些癌症的进展。基底膜和黑色素瘤的显著特点是遗传异质性和适应靶向治疗的能力。该项目试图通过靶向癌症中一种新的信号中枢--二酰甘油激酶�(DGK�)来解决这两个问题。我们先前对一种微小RNA对肾小管上皮细胞的细胞毒作用的研究使我们确定它对DGK�的击倒是其细胞毒作用的主要驱动因素，这表明了靶向这种激酶的潜在用途。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具有重要作用，进一步支持了DGK�作为靶点的潜力。我们最近报道，在体外和小鼠模型中，DGK�的敲除和小分子抑制都会导致基底膜和黑色素瘤细胞的凋亡。这些研究还表明了体内的抗血管生成作用，以及mTOR和HIF-1�作为DGK�效应在癌症中的介体的重要性。自从我们发表报告以来，我们发现一种在先前的临床试验中被发现是安全的非癌症适应症的废弃药物，利坦色林，是一种新型的DGK�抑制剂。重要的是，最近的报告表明，DGK�抑制剂具有打破T细胞无能和促进癌症免疫治疗的潜力。因此，我们假设Ritanserin和其他新型DGK�抑制剂无论是作为单一药物还是与免疫疗法联合使用，都将对黑色素瘤的基底膜和脑转移非常有效。在这项提案的目标1中，我们将测试可能的新型DGK�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研究瑞坦色林和其他新型DGK�抑制剂在小鼠肾小球基底膜和黑色素瘤移植模型中是否安全有效。在目标3中，我们将在免疫缺陷小鼠中确定这些DGK�抑制剂是否增加了局部免疫反应，并与免疫治疗有协同作用。这些拟议研究的成功完成将有助于阐明DGK�在基底膜和黑色素瘤脑转移中的生物学和治疗靶向性，并有可能迅速转化为临床试验。这一策略可能会在癌症中有广泛的应用，通过对癌细胞的直接细胞毒作用，抗血管生成作用，并加强一系列有前景的新免疫疗法。

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.