Overcoming mechanisms of therapeutic resistance in pancreatic ductal adenocarcinoma
克服胰腺导管腺癌的治疗耐药机制
基本信息
- 批准号:10629062
- 负责人:
- 金额:$ 295.32万
- 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:2023-07-06 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:Automobile DrivingAutophagocytosisBiologyBiometryBiostatistics CoreCA-19-9 AntigenCancer EtiologyCell CommunicationCell SurvivalCellsCessation of lifeChemoresistanceClinicalCoculture TechniquesCoupledCuesDNA DamageDesmoplasticDevelopmentDrug Delivery SystemsDrug resistanceEpidermal Growth Factor ReceptorEpigenetic ProcessFibroblastsGenomeGoalsGrowthHDAC1 geneHeterogeneityHistone DeacetylaseHistone Deacetylase InhibitorHumanHypoxiaImmuneImmune checkpoint inhibitorImmunotherapyIndividualInflammatoryInformaticsLIF geneMacrophageMacrophage ActivationMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMetabolicMetabolismModelingMusMutationNatureNutrient DepletionNutrient availabilityOrganoidsOutcomePancreatic Ductal AdenocarcinomaParacrine CommunicationPathway interactionsPatientsPolysaccharidesPost-Translational Protein ProcessingProductionRefractory DiseaseRegulationResearch PersonnelResearch Project GrantsResearch SupportResistanceResource SharingRoleSTAT3 geneSamplingSignal PathwaySignal TransductionSpecimenStressStromal CellsSurvival RateSystemTestingTherapeuticToxic effectTreatment EfficacyTumor PromotionVascularizationcell typecheckpoint inhibitionchemotherapycombinatorialcytokinedigitalepigenomeglycosylationimmunogenic cell deathimprovedinhibition of autophagyinhibitorinnovationinterestmortalitymouse modelnanoparticle drugneoplastic cellnovelnovel therapeuticsparacrineprogramsresistance factorsresistance mechanismresponsesingle cell analysisstemsupport networksynergismtargeted treatmenttherapy outcometherapy resistanttreatment responsetreatment strategytumortumor growthtumor microenvironmenttumorigenic
项目摘要
PROJECT SUMMARY – Overall
While mortality rates for many cancers are declining, pancreatic ductal adenocarcinoma (PDA) remains a highly
lethal malignancy with the worst 5-year survival rate of the common malignancies. Unfortunately, current
therapies are largely ineffective in PDA, an outcome attributed in large part to therapeutic resistance. The highly
fibrotic and poorly vascularized tumor microenvironment (TME) restricts both nutrient availability and drug
delivery, and provides pro-survival and immunosuppressive cues. These limitations create energy stresses that
drive metabolic adaptations to support tumor growth and therapeutic resistance. Moreover, the hyperactivation
of pro-survival and resistance pathways in tumor and stromal cell types results in an integrated resistance
network. The induction of these pathways is orchestrated by cell-to-cell communications within the TME,
including aberrant glycosylation (CA-19-9) and the secretion of immunosuppressive and pro-survival paracrine
factors, such as Leukemia Inhibitory Factor (LIF) from cancer-associated fibroblasts (CAFs). In addition, cells
adapt to the hypoxic, nutrient-depleted TME by upregulating cell type-specific survival programs, including
autophagy. Ultimately, to support and respond to these signaling and metabolic programs, both the tumor and
stromal cell epigenomes are reprogrammed, leading to cellular heterogeneity and plasticity that restricts durable
therapy responses. Each of these programs promote resistance to a broad range of therapeutics, including
chemotherapies, targeted therapies, and immune checkpoint inhibitors.
The central hypothesis of this program is that pancreatic cancer has co-opted an integrated network
of epigenetic programs, paracrine signaling pathways, and metabolic adaptations to promote tumor
survival and therapeutic resistance. Building upon the investigators’ complementary expertise in epigenetics,
cell signaling, and metabolic adaptations, as well as common interests in pancreatic cancer, this program seeks
to understand the interactions that hinder PDA therapeutic responses, with the ultimate goal of identifying
vulnerabilities that can be exploited and targeted to overcome drug resistance. Importantly, the program will
utilize advanced mono- and co-culture organoid systems, cutting-edge mouse models, novel therapeutics,
single-cell approaches, and human clinical specimens to delineate the contributions of both tumor cells and their
stromal support network to therapeutic resistance. Moreover, proposed cooperative and innovative approach will
reveal how these resistance nodes are integrated and can be targeted to improve therapeutic outcomes in PDA.
项目概要——总体
虽然许多癌症的死亡率正在下降,但胰腺导管腺癌(PDA)仍然是一个高度危险的癌症。
常见恶性肿瘤中 5 年生存率最差的致命恶性肿瘤。不幸的是,目前
治疗对于 PDA 基本上无效,这一结果在很大程度上归因于治疗耐药。高度
纤维化和血管化不良的肿瘤微环境(TME)限制了营养物质的可用性和药物
传递,并提供促生存和免疫抑制的线索。这些限制造成了能源压力
驱动代谢适应以支持肿瘤生长和治疗耐药性。此外,过度活跃
肿瘤和基质细胞类型中的促生存和耐药途径的结合导致了综合耐药性
网络。这些途径的诱导是由 TME 内的细胞间通讯精心策划的,
包括异常糖基化 (CA-19-9) 以及免疫抑制和促生存旁分泌的分泌
因子,例如来自癌症相关成纤维细胞 (CAF) 的白血病抑制因子 (LIF)。此外,细胞
通过上调细胞类型特异性生存程序来适应缺氧、营养耗尽的 TME,包括
自噬。最终,为了支持和响应这些信号传导和代谢程序,肿瘤和
基质细胞表观基因组被重新编程,导致细胞异质性和可塑性,限制了持久性
治疗反应。这些计划中的每一个都会促进对多种治疗方法的耐药性,包括
化疗、靶向治疗和免疫检查点抑制剂。
该计划的中心假设是胰腺癌已经选择了一个集成网络
表观遗传程序、旁分泌信号通路和代谢适应促进肿瘤
生存和治疗抵抗。基于研究人员在表观遗传学方面的互补专业知识,
该计划寻求细胞信号传导、代谢适应以及对胰腺癌的共同兴趣
了解阻碍 PDA 治疗反应的相互作用,最终目标是确定
可以利用和瞄准克服耐药性的脆弱性。重要的是,该计划将
利用先进的单一和共培养类器官系统、尖端的小鼠模型、新颖的疗法、
单细胞方法和人类临床标本来描绘肿瘤细胞及其贡献
基质支持网络对治疗抵抗。此外,拟议的合作和创新方法将
揭示这些耐药节点如何整合并有针对性地改善 PDA 的治疗结果。
项目成果
期刊论文数量(0)
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TONY R. HUNTER其他文献
TONY R. HUNTER的其他文献
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{{ truncateString('TONY R. HUNTER', 18)}}的其他基金
Project 2: Targeting signaling networks to overcome therapeutic resistance in pancreatic cancer
项目 2:靶向信号网络克服胰腺癌的治疗耐药性
- 批准号:
10629064 - 财政年份:2023
- 资助金额:
$ 295.32万 - 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
- 批准号:
10680390 - 财政年份:2019
- 资助金额:
$ 295.32万 - 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
- 批准号:
10228707 - 财政年份:2019
- 资助金额:
$ 295.32万 - 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
- 批准号:
10020348 - 财政年份:2019
- 资助金额:
$ 295.32万 - 项目类别:
Histidine phosphorylation as a new target for cancer therapy
组氨酸磷酸化作为癌症治疗的新靶点
- 批准号:
10450680 - 财政年份:2019
- 资助金额:
$ 295.32万 - 项目类别:
The Invisible Phosphoproteome: New Tools to Study Histidine Phosphorylation
看不见的磷酸化蛋白质组:研究组氨酸磷酸化的新工具
- 批准号:
9228357 - 财政年份:2015
- 资助金额:
$ 295.32万 - 项目类别:
The Invisible Phosphoproteome: New Tools to Study Histidine Phosphorylation
看不见的磷酸化蛋白质组:研究组氨酸磷酸化的新工具
- 批准号:
9437683 - 财政年份:2015
- 资助金额:
$ 295.32万 - 项目类别:
The Invisible Phosphoproteome: New Tools to Study Histidine Phosphorylation
看不见的磷酸化蛋白质组:研究组氨酸磷酸化的新工具
- 批准号:
9017975 - 财政年份:2015
- 资助金额:
$ 295.32万 - 项目类别: