Engineered Nanoformulation for Immune-modulation in Cancer
用于癌症免疫调节的工程纳米制剂
基本信息
- 批准号:10719487
- 负责人:
- 金额:$ 54.31万
- 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:2023-08-15 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelAnimalsAntigensAntineoplastic AgentsAntitumor ResponseApoptoticBinding ProteinsBinding SitesBreast Cancer CellCTLA4 geneCancer BiologyCancer ModelCancer PatientCancer cell lineCell Cycle ArrestCell DeathCell ProliferationCell physiologyCellsCisplatinClinicalDataDendrimersDevelopmentDisease ProgressionDrug resistanceEmbryoEngineeringExhibitsGene DeliveryGeneticGrowthHumanImmuneImmune checkpoint inhibitorImmune responseImmunoglobulinsImmunologyImmunotherapyIn VitroInvadedLaboratoriesLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMediatingMessenger RNAMicrometastasisModelingMolecularMolecular TargetMucinsMusMutagensNeoplasm MetastasisOncoproteinsPathologyPathway interactionsPromoter RegionsProtein FamilyProteinsRadiation therapyRadiosensitizationRecurrent diseaseReportingResearch PersonnelResistanceSignal TransductionSmall Interfering RNASurvival RateT cell responseT-LymphocyteTNFSF10 geneTestingTherapeuticTissuesTreatment FailureTreatment outcomeVisionanti-PD-L1anti-PD-L1 therapyanti-canceranticancer activitycancer cellcancer immunotherapycancer infiltrating T cellscancer therapycell motilitychemotherapyclinical translationeffective therapyefficacy studyimmune checkpointimmunoregulationin vivoinhibitorinnovationlipid nanoparticlelung cancer cellmRNA Expressionmembermolecular targeted therapiesmultidisciplinarynanoengineeringnanoformulationnanoparticlenanotherapyneoplastic cellnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpatient subsetspharmacologicpointed proteinpreclinical studyprogrammed cell death ligand 1programmed cell death protein 1protein expressionsiRNA deliverystatisticstargeted cancer therapytargeted treatmenttumortumor eradicationtumor growthtumor heterogeneity
项目摘要
Expression of immune check point (ICP) molecules on tumor cells and the host immune
cells, especially T-cells present in the tumor milieu, negatively impact the cancer treatment
outcome resulting in inefficient tumor eradication. Data also exist showing chemo- and radio-
therapy induce ICP proteins on tumor cells and thereby contributing to inactivation of tumor
infiltrating T-cells, resulting in the inability to host a robust antitumor response and culminating in
treatment failure, and disease recurrence. Hence, understanding how a cancer drug impacts
ICP will lead to development of new therapeutic strategies that can circumvent ICP-mediated
treatment failure. One such approach is to incorporate immune check point inhibitors (ICPi)
which can rekindle T-cell response and enhance the efficacy of anticancer drugs.
Studies from the PI's laboratory and others have demonstrated genetic and pharmacologic
inhibition of the human antigen R (HuR), an mRNA-binding protein that is overexpressed in
human cancer cells, results in growth inhibition, reduction in metastasis, and in increased
animal survival. While these findings support advancing HuR-targeted therapy for clinical
translation, the PI's lab has recently made a serendipitous discovery showing siRNA-
mediated silencing of HuR using a lipid-based nanoparticle (HuR-NP) induced programmed
death-ligand (PD-L)1 expression in lung cancer cells. PD-L1 is one among several ICP proteins
which when expressed by tumor cells suppress T-cell function. HuR-NP markedly induced PD-
L1 mRNA and protein expression in human lung cancer cell lines. Molecular studies showed
HuR binding site in the promoter region of PD-L1. Finally, a negative correlation between HuR
and PD-L1 expression was observed in human lung cancer tissues. To our knowledge, apart
from our own observation reported herein, there are no prior reports demonstrating the ability of
HuR to regulate PD-L1 and testing of HuR-nanotherapy with PD-L1 immunotherapy for cancer.
On the basis of our novel findings, we posit that combining HuR-nanotherapy with PD-L1
immunotherapy will demonstrate superior anticancer efficacy by eliciting strong immune
response, and reducing disease recurrence. We will test our hypothesis with three aims: Aim 1.
Determine the therapeutic benefit of LNP targeting HuR in combination with anti-PD-L1 therapy
in vitro. Aim 2. Demonstrate LNP targeted HuR treatment in combination with PD-L1
immunotherapy in in vivo using lung tumor models elicits immune response and enhanced
antitumor activity. Aim 3. Investigate the molecular mechanism by which LNP targeting HuR
modulates PD-L1 expression in lung cancer cells.
免疫检查点(ICP)分子在肿瘤细胞和宿主免疫上的表达
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)
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Rajagopal Ramesh其他文献
Rajagopal Ramesh的其他文献
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{{ truncateString('Rajagopal Ramesh', 18)}}的其他基金
ShEEP Request for CytoViva 3D Darkfield Hyperspectral Microscope
ShEEP 请求 CytoViva 3D 暗场高光谱显微镜
- 批准号:
9906462 - 财政年份:2019
- 资助金额:
$ 54.31万 - 项目类别:
An improved IL-24 gene-based therapeutic for cancer
改进的基于 IL-24 基因的癌症疗法
- 批准号:
10326352 - 财政年份:2019
- 资助金额:
$ 54.31万 - 项目类别:
An improved IL-24 gene-based therapeutic for cancer
改进的基于 IL-24 基因的癌症疗法
- 批准号:
10544003 - 财政年份:2019
- 资助金额:
$ 54.31万 - 项目类别:
Cancer Research Training and Education Coordination
癌症研究培训和教育协调
- 批准号:
10627028 - 财政年份:2018
- 资助金额:
$ 54.31万 - 项目类别:
Molecular Impact of Platinum Drugs on the Proteasome and SQSTM1_P62 Complexes_A Paradigm Shift in Resistance
铂类药物对蛋白酶体和 SQSTM1_P62 复合物的分子影响_耐药范式转变
- 批准号:
10051382 - 财政年份:2017
- 资助金额:
$ 54.31万 - 项目类别:
Molecular Impact of Platinum Drugs on the Proteasome and SQSTM1_P62 Complexes_A Paradigm Shift in Resistance
铂类药物对蛋白酶体和 SQSTM1_P62 复合物的分子影响_耐药范式转变
- 批准号:
9478535 - 财政年份:2017
- 资助金额:
$ 54.31万 - 项目类别:
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