Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis
用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法
基本信息
- 批准号:8786709
- 负责人:
- 金额:$ 49.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAngiogenesis InhibitorsApoptosisApoptoticAutomobile DrivingBioavailableBiological ModelsBiologyBloodBlood - brain barrier anatomyBrainBrain NeoplasmsC57BL/6 MouseCTLA4-IgCell CountCell DeathCellsClinicClinicalClinical TrialsDataDevelopmentDiacylglycerol KinaseEnzymesFamily memberFlow CytometryGeneticGenetic HeterogeneityGenetically Engineered MouseGlioblastomaGliomaHalf-LifeHeterogeneityHourHumanImageImmune responseImmunocompetentImmunotherapyIn VitroKetanserinLifeLightMalignant NeoplasmsMalignant neoplasm of brainMediatingMediator of activation proteinMelanoma CellMetastatic malignant neoplasm to brainMetastatic toMicroRNAsMicrogliaModelingMusNeoplasm MetastasisOncogenicOperative Surgical ProceduresOvalbuminPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhosphatidic AcidPhospholipidsPhosphotransferasesPrimary Brain NeoplasmsPropertyProteinsPublishingRadiationReportingResectedResistanceRitanserinRoleSCID MiceSafetySignal PathwaySignal TransductionStem cellsT cell anergyT-LymphocyteTestingTherapeuticToxic effectTransgenic OrganismsTranslationsTransplantationWorkXenograft ModelXenograft procedureactivity markeraddictionanalogangiogenesisbryostatinc-myc Genescancer cellcancer immunotherapychemotherapycytotoxiccytotoxicityexperiencehuman FRAP1 proteinin vivoinhibitor/antagonistinnovationkinase inhibitormelanomamouse modelneuro-oncologyneuroimmunologynovelpre-clinicalpublic health relevanceresistance mechanismresponsesmall moleculestandard caretemozolomidetherapeutic targettumortumor progression
项目摘要
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.
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¿及其产品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¿作为靶标的潜力。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导致GBM和黑色素瘤系细胞凋亡。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,我们发现一种在非癌症适应症的先前临床试验中被发现安全的废弃药物利坦色林是一种新型DGK抑制剂。重要的是,最近的报告表明,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抑制剂将对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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Benjamin W. Purow其他文献
Understanding current experimental models of glioblastoma-brain microenvironment interactions
- DOI:
10.1007/s11060-023-04536-8 - 发表时间:
2024-01-01 - 期刊:
- 影响因子:3.100
- 作者:
Niket Yadav;Benjamin W. Purow - 通讯作者:
Benjamin W. Purow
Isocitrate dehydrogenase mutations in low-grade gliomas
低级别胶质瘤中的异柠檬酸脱氢酶突变
- DOI:
10.1038/nrneurol.2009.57 - 发表时间:
2009-06-01 - 期刊:
- 影响因子:33.100
- 作者:
David Schiff;Benjamin W. Purow - 通讯作者:
Benjamin W. Purow
Benjamin W. Purow的其他文献
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{{ truncateString('Benjamin W. Purow', 18)}}的其他基金
Vulnerabilities of MMR-deficient glioblastoma
MMR 缺陷的胶质母细胞瘤的脆弱性
- 批准号:
10672360 - 财政年份:2022
- 资助金额:
$ 49.36万 - 项目类别:
Novel immunotherapeutic potential of DGKalpha inhibition for glioblastoma
DGKα 抑制对胶质母细胞瘤的新免疫治疗潜力
- 批准号:
10584015 - 财政年份:2022
- 资助金额:
$ 49.36万 - 项目类别:
Vulnerabilities of MMR-deficient glioblastoma
MMR 缺陷的胶质母细胞瘤的脆弱性
- 批准号:
10517124 - 财政年份:2022
- 资助金额:
$ 49.36万 - 项目类别:
Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis
用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法
- 批准号:
9111671 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
Targeting diacylglycerol kinases in glioblastoma
靶向胶质母细胞瘤中的二酰甘油激酶
- 批准号:
8709072 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis
用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法
- 批准号:
9531279 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis
用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法
- 批准号:
9320518 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis
用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法
- 批准号:
8895873 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
Novel DGKalpha inhibitors and immunotherapy for GBM and melanoma brain metastasis
用于 GBM 和黑色素瘤脑转移的新型 DGKα 抑制剂和免疫疗法
- 批准号:
9649402 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
Targeting diacylglycerol kinases in glioblastoma
靶向胶质母细胞瘤中的二酰甘油激酶
- 批准号:
8846074 - 财政年份:2014
- 资助金额:
$ 49.36万 - 项目类别:
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