Small-molecule exploitation of ZBP1-driven nuclear necroptosis for cancer immunotherapy
ZBP1 驱动的核坏死性凋亡的小分子开发用于癌症免疫治疗
基本信息
- 批准号:10586659
- 负责人:
- 金额:$ 75.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:Abscopal effectAdjuvantAffinityAgonistAntitumor ResponseArchitectureBindingBiologyCell DeathCell Death Signaling ProcessCell NucleusCellsChromatinChromatin StructureClinicalCytoplasmDNADataDoseDouble-Stranded RNAEukaryotic CellExtracellular SpaceFibroblastsGenetically Engineered MouseGenomic DNAGoalsHistonesImmuneImmune systemImmunologic AdjuvantsImmunotherapyInflammatoryInfluenza A virusInnate Immune ResponseInterphase CellLeftLigandsLinker DNAMalignant NeoplasmsMediatingModalityMolecular ChaperonesMolecular ConformationNeoplasm MetastasisNuclearNucleosomesPathway interactionsPatientsProcessProteinsRIPK3 geneRNAReportingResearchRoleRouteRuptureSignal PathwaySignal TransductionT cell responseT-LymphocyteTestingTreatment outcomeUV-induced melanomaUbiquitinationViralVirus DiseasesWorkXenograft procedureZ-Form DNAanti-PD-1cancer immunotherapycancer therapycell killingcell typeclinically relevantcombinatorialgenome-wideimmune checkpoint blockadeimmunogenicimmunogenicityimprovedintercalationmelanomamouse modelneoantigensneoplastic cellrecruitsensorsmall moleculetheoriestumortumor microenvironmentviral RNAviral detection
项目摘要
PROJECT SUMMARY/ABSTRACT.
Immune checkpoint blockade (ICB) and other immunotherapies have revolutionized cancer treatment, but the
non-responsiveness of most cancers to ICB-based monotherapy remains a significant problem. A major reason
for the non-responsiveness of these so-called ‘cold’ tumors is that they lack an immunogenic tumor
microenvironment (TME) and thus escape T-cell killing despite expressing ICB targets. How to selectively
intensify the immunogenicity of the TME has been an unmet challenge. Here we propose a new small-molecule
approach that activates necroptosis and triggers robust innate immune responses in the TME. This new avenue
derives from our work on influenza A virus (IAV). Our early findings showed that IAV activates necroptosis in
infected cells. Necroptosis kills infected cells and is highly immunogenic. It is initiated when viral RNAs activating
the host protein ZBP1. Recently, and highly relevant for cancer immunotherapy, we found that ZBP1 activates
necroptosis from the nucleus. Such ‘nuclear necroptosis’ is significantly more immunogenic than conventional
(cytoplasm-initiated) necroptosis because it ruptures the nucleus and releases hyper-inflammatory nuclear
DAMPs into the extracellular space. We also found that the viral RNAs that activate ZBP1 are Z-RNAs. Although
these unique ZBP1 activators should be superb adjuvants for ICB, Z-RNA is unstable and hard to produce absent
virus infection. Z-DNA, however, is structurally almost identical to Z-RNA, binds ZBP1 with the same affinity, and
can be stably produced in eukaryotic cells by distorting DNA into the Z-conformation. This suggested that a
compound that can generate Z-DNA in cells would activate ZBP1 and trigger on-demand nuclear necroptosis
without need for virus infection. Such a compound would fill the long-unmet need for a necroptosis agonist for
use in cancer immunotherapy. We have now identified a small molecule, curaxin, which induces Z-DNA
formation in live cells and directly activates ZBP1 to trigger ‘on-demand’ nuclear necroptosis in cells of the TME.
These and other findings allow us to propose the hypotheses that curaxin alters chromatin structure and induces
the formation of Z-DNA; that such Z-DNA recruits ZBP1 to the nucleus and triggers nuclear necroptosis; and that
curaxin-induced nuclear necroptosis will greatly improve ICB treatment outcomes. In this proposal, we will ask
how curaxin triggers Z-DNA formation (Aim 1), how Z-DNA activates ZBP1 and nuclear necroptosis (Aim 2), and
whether induction of nuclear necroptosis by curaxin has combinatorial benefit with ICB in clinically-relevant
mouse models of melanoma (Aim 3). The successful completion of these Aims will outline an entirely new small-
molecule based strategy to activate a highly inflammatory form of necroptosis and potentiate ICB-based
immunotherapies, with important clinical ramifications.
项目摘要/摘要。
免疫检查点阻断(ICB)和其他免疫疗法彻底改变了癌症治疗,但
大多数癌症对基于 ICB 的单一疗法无反应仍然是一个重大问题。一个主要原因
这些所谓的“冷”肿瘤的无反应性是因为它们缺乏免疫原性肿瘤
尽管表达了 ICB 靶标,但微环境 (TME) 仍逃脱了 T 细胞杀伤。如何有选择地
增强TME的免疫原性一直是一个未解决的挑战。在这里我们提出了一种新的小分子
激活坏死性凋亡并触发 TME 中强大的先天免疫反应的方法。这条新大道
源自我们对甲型流感病毒 (IAV) 的研究。我们的早期研究结果表明,IAV 会激活坏死性凋亡
被感染的细胞。坏死性凋亡会杀死受感染的细胞,并且具有高度免疫原性。当病毒RNA激活时就会启动
宿主蛋白ZBP1。最近,与癌症免疫疗法高度相关的是,我们发现 ZBP1 激活
来自细胞核的坏死性凋亡。这种“核坏死性凋亡”比传统的“核坏死性凋亡”具有更高的免疫原性。
(细胞质引发的)坏死性凋亡,因为它会破裂细胞核并释放高炎症细胞核
DAMP 进入细胞外空间。我们还发现激活ZBP1的病毒RNA是Z-RNA。虽然
这些独特的 ZBP1 激活剂应该是 ICB 的极好佐剂,Z-RNA 不稳定且难以生产。
病毒感染。然而,Z-DNA 在结构上几乎与 Z-RNA 相同,以相同的亲和力结合 ZBP1,并且
通过将 DNA 扭曲成 Z 构象,可以在真核细胞中稳定产生。这表明
可以在细胞中产生 Z-DNA 的化合物会激活 ZBP1 并触发按需核坏死性凋亡
无需病毒感染。这种化合物将满足长期以来对坏死性凋亡激动剂的需求。
在癌症免疫治疗中的应用。我们现在已经鉴定出一种小分子,curaxin,它可以诱导 Z-DNA
活细胞中形成并直接激活 ZBP1 以触发 TME 细胞中的“按需”核坏死性凋亡。
这些和其他发现使我们能够提出这样的假设:curaxin 改变染色质结构并诱导
Z-DNA的形成;这种 Z-DNA 将 ZBP1 招募到细胞核并引发核坏死性凋亡;还有那个
curaxin 诱导的核坏死性凋亡将大大改善 ICB 治疗结果。在这个提案中,我们会问
curaxin 如何触发 Z-DNA 形成(目标 1),Z-DNA 如何激活 ZBP1 和核坏死性凋亡(目标 2),以及
curaxin 诱导核坏死性凋亡是否与 ICB 在临床相关方面具有联合益处
黑色素瘤小鼠模型(目标 3)。这些目标的成功实现将勾画出一个全新的小型
基于分子的策略,激活高度炎症形式的坏死性凋亡并增强基于 ICB 的效果
免疫疗法具有重要的临床意义。
项目成果
期刊论文数量(0)
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SIDDHARTH BALACHANDRAN其他文献
SIDDHARTH BALACHANDRAN的其他文献
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{{ truncateString('SIDDHARTH BALACHANDRAN', 18)}}的其他基金
Harnessing ZBP1-triggered cell death to enhance influenza vaccine responsiveness
利用 ZBP1 触发的细胞死亡来增强流感疫苗的反应性
- 批准号:
10884586 - 财政年份:2023
- 资助金额:
$ 75.9万 - 项目类别:
Role of ZBP1 in pathogenesis of Salmonella biofilms
ZBP1 在沙门氏菌生物膜发病机制中的作用
- 批准号:
10658383 - 财政年份:2023
- 资助金额:
$ 75.9万 - 项目类别:
Necroptosis in SARS-CoV-2 pathogenesis, evolution, and therapy
SARS-CoV-2 发病机制、进化和治疗中的坏死性凋亡
- 批准号:
10557863 - 财政年份:2022
- 资助金额:
$ 75.9万 - 项目类别:
Necroptosis in SARS-CoV-2 pathogenesis, evolution, and therapy
SARS-CoV-2 发病机制、进化和治疗中的坏死性凋亡
- 批准号:
10433040 - 财政年份:2022
- 资助金额:
$ 75.9万 - 项目类别:
Harnessing ZBP1-driven cell death to improve influenza vaccine efficacy
利用 ZBP1 驱动的细胞死亡来提高流感疫苗的功效
- 批准号:
10455196 - 财政年份:2021
- 资助金额:
$ 75.9万 - 项目类别:
Targeting RIPK3 in Flu-Associated Lung Injury
靶向 RIPK3 治疗流感相关肺损伤
- 批准号:
10020307 - 财政年份:2019
- 资助金额:
$ 75.9万 - 项目类别:
Targeting RIPK3 in Flu-Associated Lung Injury
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- 批准号:
10470746 - 财政年份:2019
- 资助金额:
$ 75.9万 - 项目类别:
Targeting RIPK3 in Flu-Associated Lung Injury
靶向 RIPK3 治疗流感相关肺损伤
- 批准号:
10689229 - 财政年份:2019
- 资助金额:
$ 75.9万 - 项目类别:
Targeting RIPK3 in Flu-Associated Lung Injury
靶向 RIPK3 治疗流感相关肺损伤
- 批准号:
10238084 - 财政年份:2019
- 资助金额:
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- 批准号:
10247652 - 财政年份:2017
- 资助金额:
$ 75.9万 - 项目类别:
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