Mechanisms of cell death in cutaneous melanoma
皮肤黑色素瘤细胞死亡的机制
基本信息
- 批准号:10316444
- 负责人:
- 金额:$ 47.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdjuvantAffectAntibodiesApoptosisApoptoticBRAF geneBioinformaticsBiological AssayBiologyCASP3 geneCD8-Positive T-LymphocytesCaspaseCell DeathCell TherapyCellsCleaved cellClinicalClinical DataClinical TrialsCollaborationsCommunicationComplementCutaneous MelanomaDNADataDendritic CellsDendritic cell tumorDisease ResistanceDrug ToleranceEatingExcisionExclusionExhibitsFDA approvedGoalsGrowthHigh Mobility Group ProteinsImmuneImmune checkpoint inhibitorImmune responseImmune systemImmunotherapyIncidenceKnock-outKnockout MiceLeukocytesLinkMEKsMalignant NeoplasmsMediatingMelanoma CellModelingMolecularNatureNivolumabPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacologyPhosphorylationPopulationProcessPublishingQuality of lifeRegimenRegulationResidual NeoplasmResidual TumorsResistanceRoleSignal PathwaySignal TransductionStressT-LymphocyteTP53 geneTestingTherapeuticToxic effectTumor-infiltrating immune cellsWorkadaptive immune responseanti-CTLA4anti-PD-1anti-tumor immune responsebasecancer cellcancer therapycheckpoint inhibitioncheckpoint therapychemotherapycytokinedesignimmune checkpointimmunogenicimmunogenic cell deathimmunogenicityimprovedin vivoin vivo Modelinducible gene expressioninhibitor/antagonistinsightipilimumabmelanomamultidisciplinarymutantneoantigensneoplastic cellnovelnovel therapeutic interventionpembrolizumabpre-clinicalpreventresistance mechanismresponsesingle cell analysissmall moleculestandard of caresynergismtargeted treatmenttreatment responsetreatment strategytumortumor growthtumor-immune system interactions
项目摘要
PROJECT SUMMARY
The incidence of cutaneous melanoma is rising. While small molecule targeted inhibitors and immune
checkpoint antibodies have increased long-term survival in advanced-stage cutaneous melanoma, many
patients still do not benefit and regimens are associated with high toxicity. We are studying the determinants
of treatment response and mechanisms of resistance in melanoma. From our studies, we aim to generate pre-
clinical data for new combinations that delay/prevent the onset of acquired resistance while minimizing patient
toxicities in order to improve patient survival and quality of life. Multiple clinical trials have emanated from our
work (NCT03580382, NCT02012231, NCT02683395). Tumor immunogenicity, defined as the ability of the
tumor itself to trigger an anti-tumor adaptive immune response, is one of the most important determinants of
successful anti-cancer therapy. The immunogenicity of a tumor depends on its antigenicity, conferred by neo-
antigens, and also by adjuvant effects triggered by damage-associated molecular patterns (DAMPs) released
from stressed or dying tumor cells during a process called immunogenic cell death (ICD). We recently
discovered a signaling pathway that allows efficient release of DAMPs from dying cells by switching apoptosis
into a potentially immunogenic form of cell death called pyroptosis. Mechanistically, activation of caspase-3
during apoptosis leads to cleavage of gasdermin E (GSDME), generating a pore-forming GSDME-N fragment.
GSDME-N pores allow release of intracellular DAMPs such as HMGB1, DNA, and ATP. The ability of this
novel pathway to switch apoptosis into pyroptosis suggests that GSDME-induced pyroptosis is likely a key
effector of cancer cell immunogenicity and may determine their successful response to various anti-cancer
therapies. Supporting this hypothesis, our preliminary data revealed that efficient BRAFi + MEKi-induced anti-
tumor immune responses in melanoma cells are dependent, at least in part, on the pyroptotic activity of
GSDME. The goals of this application are to define mechanisms underlying BRAFi + MEKi regulation of
GSDME and pyroptosis in melanoma and to investigate how GSDME-induced pyroptosis alters the effects of
immune checkpoint inhibitors. The standard of care for melanomas is immune checkpoint inhibition, specifically
anti-PD-1 (pembrolizumab and nivolumab) and anti-CTLA-4 (ipilimumab). Immune checkpoint inhibitors are
efficacious in some melanoma patients; however, many do not respond. Other patients who initially respond,
ultimately progress. This proposal is designed to utilize targeted therapies to optimize up-front immune
checkpoint inhibitors as well as invigorating the immune system in resistant tumors. Thus, we aim to develop
new therapeutic strategies that will address clinical unmet needs in the melanoma field.
项目摘要
皮肤黑色素瘤的发生率正在上升。而小分子靶向抑制剂和免疫
检查点抗体在晚期皮肤黑色素瘤中长期生存增加,许多
患者仍然没有受益,方案与高毒性有关。我们正在研究决定因素
治疗反应和黑色素瘤耐药性的机制。从我们的研究中,我们旨在产生前
新组合的临床数据,这些组合延迟/阻止获得的抗药性发作,同时最大程度地减少患者
毒性以改善患者的生存和生活质量。我们的多次临床试验已经从我们的
工作(NCT03580382,NCT02012231,NCT02683395)。肿瘤免疫原性,定义为
肿瘤本身触发抗肿瘤的自适应免疫反应,是最重要的决定因素之一
成功的抗癌疗法。肿瘤的免疫原性取决于其抗原性,由新肿瘤赋予
抗原,以及由释放的损伤相关分子模式触发的佐剂作用
在称为免疫生成细胞死亡(ICD)的过程中,应受到压力或垂死的肿瘤细胞。我们最近
发现了一个信号通路,该途径允许通过切换凋亡从垂死的细胞中有效释放潮湿
变成一种可能免疫原性的细胞死亡形式,称为凋亡。从机械上讲,caspase-3的激活
在凋亡过程中,导致Gasdermin E(GSDME)的裂解,产生形成孔的GSDME-N片段。
GSDME-N孔允许释放细胞内潮湿,例如HMGB1,DNA和ATP。这个能力
将细胞凋亡转换为凋亡的新途径表明,GSDME诱导的凋亡可能是关键
癌细胞免疫原性的效应因子,可以确定它们对各种抗癌者的成功反应
疗法。支持这一假设,我们的初步数据表明,有效的BRAFI + MEKI诱导的抗抗
黑色素瘤细胞中的肿瘤免疫反应至少部分取决于
GSDME。此应用的目标是定义BRAFI + MEKI的基础机制
GSDME和黑色素瘤中的凋亡,并研究GSDME诱导的凋亡如何改变
免疫检查点抑制剂。黑色素瘤的护理标准是免疫检查点抑制,特别是
抗PD-1(pembrolizumab和nivolumab)和抗CTLA-4(ipilimumimab)。免疫检查点抑制剂是
一些黑色素瘤患者有效;但是,许多人没有回应。其他最初反应的患者,
最终进步。该建议旨在利用靶向疗法来优化前期免疫力
检查点抑制剂以及抗性肿瘤中的免疫系统。因此,我们旨在发展
新的治疗策略将解决黑色素瘤领域的临床未满足需求。
项目成果
期刊论文数量(0)
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Emad S Alnemri其他文献
Emad S Alnemri的其他文献
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{{ truncateString('Emad S Alnemri', 18)}}的其他基金
Mechanisms of cell death in cutaneous melanoma
皮肤黑色素瘤细胞死亡的机制
- 批准号:
10612054 - 财政年份:2021
- 资助金额:
$ 47.78万 - 项目类别:
Mechanisms of cell death in cutaneous melanoma
皮肤黑色素瘤细胞死亡的机制
- 批准号:
10428658 - 财政年份:2021
- 资助金额:
$ 47.78万 - 项目类别:
Regulation of the Cell Death Program by DFNA5
DFNA5 对细胞死亡程序的调节
- 批准号:
10531607 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
Regulation of the Cell Death Program by DFNA5
DFNA5 对细胞死亡程序的调节
- 批准号:
10307533 - 财政年份:2019
- 资助金额:
$ 47.78万 - 项目类别:
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