Biology of major folate transporters and STING signaling in cancer
主要叶酸转运蛋白的生物学和癌症中的 STING 信号传导
基本信息
- 批准号:10597540
- 负责人:
- 金额:$ 7.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-05 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adenosine MonophosphateAgonistAnionsAreaBacteriaBiologyCD8B1 geneCell membraneCell modelCellsClinicalClinical DataClinical TrialsCodeComplexCoupledCyclic GMPCytosolDNADinucleoside PhosphatesDoseEndoplasmic ReticulumEnsureEnvironmentEpigenetic ProcessFolic AcidFolic Acid DeficiencyFrequenciesGenetic PolymorphismGenetic TranscriptionGenomicsGoalsHumanImmuneImmune checkpoint inhibitorInfectionInfiltrationInflammatory ResponseInterferon Type IInterferonsInvestigational DrugsLesionLymphomaMalignant NeoplasmsMammalian CellMethotrexateMolecularMusPathway interactionsPatientsPemetrexedPeriodicityPhase I Clinical TrialsPhysiologicalPositioning AttributePost-Transcriptional RegulationProtonsPublishingRadiation therapyRegulationReportingResearchRoleSLC19A1 geneSignal TransductionSolid NeoplasmSourceSpecificityStimulator of Interferon GenesStructureSubstrate SpecificitySystemT-LymphocyteTetrahydrofolatesTherapeuticTherapeutic EffectTissuesTumor Immunityanalogcancer cellcancer immunotherapycheckpoint therapyclinical efficacyclinical translationcytokineds-DNAextracellularfolate-binding proteinhuman tissueimmunogenicityimprovedinhibitor therapyinnate immune sensinginsightneoplastic cellnoveloverexpressionpharmacologicpre-clinicalpreclinical studypromoterprotein protein interactionresponsesensorsuccesssymportertooltumortumor growthuptake
项目摘要
ABSTRACT
In mammalian cells, cyclic dinucleotides (CDNs) act as prominent danger signals that are sensed by the innate
immune sensor, stimulator of interferon genes (STING). Activation of STING elicits a signaling cascade that
culminates in the induction of type I interferons (IFNs) and various cytokines, thereby promoting a powerful
inflammatory response. Mammalian cells are able to produce their own CDNs, catalyzed by the cyclic guanosine
monophosphate–adenosine monophosphate (GMP-AMP) synthase (cGAS), which is activated by double-strand
DNAs to synthesize the eukaryotic CDN, 2′3′-cGAMP. Beyond intracellular CDNs, STING-activating CDNs can
originate from extracellular sources, such as therapeutic CDNs, cGAMP produced by tumor cells, and CDNs from
extracellular bacteria. The role of the cGAS-STING pathway in anti-tumor immunity supports the use of STING
agonists as cancer therapeutics. Inspired by the discovery that 2′3′-cGAMP activates human STING to initiate
robust downstream IFN signaling, STING-activating agents (mostly 2′3′-cGAMP analogues) were synthesized.
Direct pharmacologic activation of STING was shown to restrict tumor growth by a T cell-driven tumor
regression mechanism and to enhance immunogenicity. Administration of cGAMP in tumor-bearing mice also
potentiated the therapeutic effects of immune-checkpoint inhibitors and radiotherapy. Based on results with
CDN analogs in mice, two phase I clinical trials were initiated for the intra-tumoral delivery of STING agonists
(ADU-S100 and MK-1454) to solid tumors and lymphomas. Despite the impressive anti-tumor activity of STING
agonists in mice, initial results from clinical trials of such agonists have indicated a lower efficacy in humans.
The regulatory interplay among the import, export and degradation of CDNs remains an important and
interesting area for future research. Exogenous 2′3′-cGAMP and synthetic CDNs, including the investigational
new drug (IND) 2′3′-CDAS used in cancer immunotherapy, traverse the cell membrane through the reduced
folate carrier (RFC; SLC19A1) to activate STING in target cells, and the proton-coupled folate transporter (PCFT;
SLC46A1) enhances such response. RFC and PCFT are major facilitative transporters of folate in human tissues
and tumors. PCFT is unique from RFC in that it has an acidic rather than neutral pH optimum. RFC and PCFT
share substrates such as clinically used methotrexate and pemetrexed but also show their own unique substrate
specificities. Our group has studied RFC and PCFT structure, function and regulation extensively. In this R03
application, we explore the unique biology of RFC, as well as PCFT, and STING agonists in cancer, with a goal
of further understanding CDN uptake by these facilitative transporters and, by extension, improving
therapeutic applications. We propose in Aim 1 to study mechanisms of CDN uptake by RFC and PCFT under
physiological conditions. In Aim 2, we will study the molecular regulation of RFC in relation to CDN uptake,
including transcriptional epigenetics, and the potential role of protein-protein interactions in regulating RFC.
Our proposed studies are distinctive for their novelty and potential for clinical translation.
摘要
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 }}
Zhanjun Hou其他文献
Zhanjun Hou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('Zhanjun Hou', 18)}}的其他基金
Biology of major folate transporters and STING signaling in cancer
主要叶酸转运蛋白的生物学和癌症中的 STING 信号传导
- 批准号:
10435010 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Molecular Regulation of Folate and Antifolate Transport
叶酸和抗叶酸转运的分子调节
- 批准号:
10652998 - 财政年份:1993
- 资助金额:
$ 7.7万 - 项目类别:
Molecular Regulation of Folate and Antifolate Transport
叶酸和抗叶酸转运的分子调节
- 批准号:
10438789 - 财政年份:1993
- 资助金额:
$ 7.7万 - 项目类别:
Molecular Regulation of Folate and Antifolate Transport
叶酸和抗叶酸转运的分子调节
- 批准号:
9025683 - 财政年份:1993
- 资助金额:
$ 7.7万 - 项目类别:
Molecular Regulation of Folate and Antifolate Transport
叶酸和抗叶酸转运的分子调节
- 批准号:
10163805 - 财政年份:1993
- 资助金额:
$ 7.7万 - 项目类别:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 7.7万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 7.7万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别:
Fentanyl Addiction: Individual Differences, Neural Circuitry, and Treatment with a GLP-1 Receptor Agonist
芬太尼成瘾:个体差异、神经回路和 GLP-1 受体激动剂治疗
- 批准号:
10534864 - 财政年份:2023
- 资助金额:
$ 7.7万 - 项目类别: