Identification of Druggable Targets to Complement Melanoma Therapy
确定可补充黑色素瘤治疗的药物靶点
基本信息
- 批准号:10163815
- 负责人:
- 金额:$ 34.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntitumor ResponseAutoimmunityBioinformaticsBiologyBiometryBiopsyCTLA4 geneCenters of Research ExcellenceCombined Modality TherapyComplementCoupledCutaneousData AnalysesDermatopathologyDiseaseDrug DesignEpigenetic ProcessGenetic TranscriptionGoalsHistonesHomeostasisImmune checkpoint inhibitorImmune systemImmunological ModelsImmunotherapyIntelligenceInvestigationLaboratoriesMass Spectrum AnalysisMolecularMonoclonal AntibodiesNivolumabOncologyOperative Surgical ProceduresPathway interactionsPatientsPositioning AttributePost-Translational Protein ProcessingProteinsProteomicsReportingResistanceResolutionResourcesSurvival RateSystems BiologyTissuesUnited States National Institutes of Healthcell typecheckpoint therapycomputer clusterdruggable targethistone modificationipilimumabmass spectrometermelanomaneoplastic cellpatient responsepatient subsetspembrolizumabpre-clinicalpreventprogrammed cell death protein 1relapse patientsresponders and non-respondersresponsestandard of caresuccesstumor immunology
项目摘要
Abstract
Historically, treatment options for melanoma were limited, and 5-year survival rates were <10% for
patients with advanced-stage disease. Recently, immune checkpoint inhibitors (ICIs) have shown encouraging
success for treatment of melanoma. However, approximately 40% of patients with advanced melanoma have
primary ICI resistance and sub-populations of initially responding patients develop secondary resistance. Can
we identify druggable molecular pathways in these non-responders to increase their ICI responsiveness and
potentially save lives? We have performed the only reported proteomics investigation of pre-ICI treatment
melanoma biopsies from responders and non-responders (6). In this preliminary study, we were able to
identify a panel of protein and histone epigenetic signatures that provided evidence for dysregulated
molecular pathways correlated to ICI responsiveness – providing the scientific premise for the outlined
studies. This preliminary study will be expanded to include 1) a larger number of patients, 2) patients with
primary and secondary ICI therapy resistance, and 3) tumor cell-type analyses. The overall goal of this
proposal is to combine state-of-the-art proteomics of patient tissues with pre-clinical animal models of ICI
responsiveness to create a functional proteomics pipeline for uncovering cellular protein and histone epigenetic
pathways functionally dysregulated in melanoma ICI non-responders. We will use a rigorous strategy to target
gene transcription and histone modifying proteins as these are upstream pathway effectors that can be
druggable. We hypothesize that certain proteins involved in gene transcription and posttranslational modification
of histones will be dysregulated in ICI non-responders and functionally coupled to molecular mechanisms of ICI
responsiveness, which will identify these proteins as high-priority, druggable candidates for complementing
existing ICI therapy. The aims of this study are: 1) perform functional proteomics to identify dysregulated gene
transcription protein pathways in melanoma ICI non-responders, 2) use high-resolution mass spectrometry to
identify dysregulated histone modifying protein pathways in melanoma ICI non-responders, and 3) determine
the functional significance in antitumor responses to ICI therapy for gene transcription and histone modifying
proteins dysregulated in melanoma ICI non-responders.
摘要
从历史上看,黑色素瘤的治疗选择是有限的,5年生存率<10%,
晚期疾病患者。最近,免疫检查点抑制剂(ICI)显示出令人鼓舞的
成功治疗黑色素瘤。然而,大约40%的晚期黑素瘤患者
原发性ICI耐药和最初应答患者的亚群发展为继发性耐药。可以
我们在这些无应答者中鉴定了可药物化的分子途径,以增加他们的ICI反应性,
有可能拯救生命吗我们进行了唯一报道的ICI前治疗的蛋白质组学研究
应答者和非应答者的黑素瘤活检(6)。在这项初步研究中,我们能够
鉴定了一组蛋白质和组蛋白表观遗传特征,这些特征为调节异常提供了证据。
与ICI反应相关的分子途径-为概述的
问题研究这项初步研究将扩大到包括1)更多数量的患者,2)
原发性和继发性ICI治疗抗性,和3)肿瘤细胞类型分析。这个项目的总体目标是
建议将联合收割机患者组织的最新蛋白质组学与ICI的临床前动物模型相结合
响应创建功能蛋白质组学管道,以揭示细胞蛋白质和组蛋白表观遗传
黑色素瘤ICI无应答者中功能失调的通路。我们将采取严格的战略,
基因转录和组蛋白修饰蛋白,因为它们是上游途径效应物,
可下药的我们假设某些参与基因转录和翻译后修饰的蛋白质
组蛋白的表达将在ICI无应答者中失调,并在功能上与ICI的分子机制相关联。
反应,这将确定这些蛋白质作为高优先级,可药用的候选人,以补充
现有ICI疗法。本研究的主要目的是:1)利用功能蛋白质组学技术,筛选出表达异常的基因
黑色素瘤ICI无应答者中的转录蛋白途径,2)使用高分辨率质谱,
鉴定黑色素瘤ICI无应答者中失调的组蛋白修饰蛋白途径,和3)确定
基因转录和组蛋白修饰在ICI抗肿瘤治疗中的作用
黑色素瘤ICI无应答者中失调的蛋白质。
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(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alan Tackett其他文献
Alan Tackett的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alan Tackett', 18)}}的其他基金
Identification of Druggable Targets to Complement Melanoma Therapy
确定可补充黑色素瘤治疗的药物靶点
- 批准号:
10630160 - 财政年份:2019
- 资助金额:
$ 34.79万 - 项目类别:
Identification of Druggable Targets to Complement Melanoma Therapy
确定可补充黑色素瘤治疗的药物靶点
- 批准号:
10412077 - 财政年份:2019
- 资助金额:
$ 34.79万 - 项目类别:
Center for Translational Pediatric Research (CTPR)
转化儿科研究中心 (CTPR)
- 批准号:
10380963 - 财政年份:2017
- 资助金额:
$ 34.79万 - 项目类别:
Center for Translational Pediatric Research (CTPR): Enhancing SARS-CoV-2 Sequencing Efforts for Variants in the State of Arkansas
转化儿科研究中心 (CTPR):加强阿肯色州 SARS-CoV-2 变异体的测序工作
- 批准号:
10595406 - 财政年份:2017
- 资助金额:
$ 34.79万 - 项目类别:
相似海外基金
Potentiating a systemic antitumor response by interstitial localized ablative immunotherapy to synergize with immune checkpoint therapy for metastatic pancreatic tumors
通过间质局部消融免疫疗法增强全身抗肿瘤反应,与转移性胰腺肿瘤的免疫检查点疗法协同作用
- 批准号:
10580071 - 财政年份:2022
- 资助金额:
$ 34.79万 - 项目类别:
Development of new cancer treatment utilizing the enhancement of antitumor response caused by allo reaction
利用同种异体反应增强抗肿瘤反应开发新的癌症治疗方法
- 批准号:
20K17649 - 财政年份:2020
- 资助金额:
$ 34.79万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Role of CD4 T cells and APCs in the induction and maintenance of an effective antitumor response
CD4 T 细胞和 APC 在诱导和维持有效抗肿瘤反应中的作用
- 批准号:
nhmrc : 143674 - 财政年份:2001
- 资助金额:
$ 34.79万 - 项目类别:
NHMRC Project Grants
ANTICD20 MEDIATED SIGNALING AND ANTITUMOR RESPONSE
ANTICD20 介导的信号传导和抗肿瘤反应
- 批准号:
2377164 - 财政年份:1997
- 资助金额:
$ 34.79万 - 项目类别:
ANTICD20 MEDIATED SIGNALING AND ANTITUMOR RESPONSE
ANTICD20 介导的信号传导和抗肿瘤反应
- 批准号:
2712876 - 财政年份:1997
- 资助金额:
$ 34.79万 - 项目类别: