Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer
Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer
批准号:
10707541
负责人:
Pankaj Kumar Singh
金额:
$24.65万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-20 至 2027-08-31
关键词:
AcidityAddressAdenosineAmino AcidsAnabolismArginineArginine deiminaseBlood VesselsCRISPR libraryCRISPR screenCancer EtiologyCell LineCellsCessation of lifeChargeChemoresistanceCirculationClinicalComplementDataDevelopmentDiagnosisDiffusionEpigenetic ProcessEventFeedsFutureGenerationsGenesGenetic TranscriptionGlucoseGlycolysis InhibitionHumanHypoxiaImmuneIntercellular FluidInvadedMalignant neoplasm of pancreasMediatingMetabolicMetabolic PathwayMetabolismMyeloid-derived suppressor cellsOncogenicOrganoidsOxidative PhosphorylationPancreatic Ductal AdenocarcinomaPathway interactionsPatientsPhenotypePhosphoglycerate dehydrogenasePost-Translational Protein ProcessingPrediction of Response to TherapyProductionPrognosisProteinsProteomicsPurinesRegulationRelapseResistanceResistance developmentRoleSerineSideSignal TransductionSiteSpecimenStromal NeoplasmT-Cell ActivationTestingTherapeuticUnited Statesacquired immunityalpha ketoglutaratechemotherapydeprivationecto-nucleotidasegenetic signaturegenome-widehuman tissueimprovedinsightknock-downneoplastic cellnovelnovel therapeuticspancreatic ductal adenocarcinoma cellpancreatic neoplasmpatient derived xenograft modelpatient prognosispredictive markerpreventprogramsprotein protein interactionrecruitresponsetherapy resistanttissue resourcetreatment responsetumortumor microenvironmenttumorigenic
中文摘要
项目总结:早期全身播散,异常局部侵袭,晚期诊断,
对现有化疗的反应导致胰腺导管腺癌预后不良
(PDAC)患者。虽然胰腺肿瘤通常显示出对化疗的低内在反应,但大多数胰腺肿瘤都是化疗的结果。
在治疗过程中获得抵抗力。因此,迫切需要了解
有助于获得性耐药性的机制,并确定新的疗法/治疗
联合用药可以显著提高患者的生存率。我们已经证明代谢
重编程为消除获得性耐药性和改善治疗提供了一个有针对性的弱点,
PDAC中的响应。治疗抗性取决于肿瘤细胞内在机制和代谢调节机制。
以及肿瘤细胞和肿瘤微环境之间的信号串扰。我们的无偏见的初步数据,
多个人PDAC患者来源的异种移植物模型鉴定肽基精氨酸脱亚胺酶1(PADI 1)为
top上调基因与患者预后不良显著相关。瓜氨酸或脱亚氨基化
精氨酸残基产生正电荷的损失,增加氨基酸的质量和酸度
侧链,并且翻译后修饰导致改变的蛋白质-蛋白质相互作用,信号传导,
转录反应。我们注意到PADI1在人PDAC肿瘤和细胞系中的强表达,
与患者生存率的相关性。抑制PADI活性或PADI 1敲低显著改善了PADI的表达。
PDAC细胞系和类器官对FOLFIRINOX治疗组分的反应性。PADI1表达
糖酵解表型和缺氧基因也与PDAC肿瘤有显著相关性
签名,显示与氧化磷酸化的相互关系。我们还进行了一个无偏见的
CRISPR筛选并鉴定了可能有效用于与药物共靶向的新代谢脆弱性
抑制PADI1下游代谢途径。PADI的表达也与细胞的重编程有关。
微环境中的免疫和非免疫基质。因此,拟议的项目1将检验假设
如果靶向PADI1或下游代谢重编程将消除耐药性的发展,
PDAC中的FOLFIRINOX。我们还将研究PDAC中基质重塑的机制基础
肿瘤和间质重编程导致获得性FOLFIRINOX耐药。我们提出
三个具体目标来检验假设。目的1将研究靶向PADI 1下游的功效
间质重塑的途径和相关机制,以消除对FOLFIRINOX治疗的耐药性。
目的2将确定肿瘤细胞内在代谢重编程的机制,这种机制也会进入基质,
由PADI1重新编程。目标3将研究目标1和2中确定的靶向途径的有效性
在PDX模型中,并利用人体组织样本确定临床相关性。这些研究将提供
针对PDAC中获得性FOLFIRINOX耐药性的新见解和机会。
英文摘要
Project Summary: Early systemic dissemination, extraordinary local invasion, late diagnosis, and inadequate
response to the existing chemotherapy contribute to poor prognosis for pancreatic ductal adenocarcinoma
(PDAC) patients. While pancreatic tumors generally show a low intrinsic response to chemotherapies, most
acquire resistance over the course of the treatment. Hence, there is an urgent need to understand the
mechanisms contributing to acquired resistance to therapies and to identify novel therapies/therapeutic
combinations that would significantly improve survival in patients. We have demonstrated that metabolic
reprogramming presents a targetable vulnerability for abrogating acquired resistance and improving the therapy
response in PDAC. The therapy resistance depends on both tumor cell-intrinsic mechanisms and a metabolic
and signaling crosstalk between tumor cells and tumor microenvironment. Our unbiased preliminary data with
multiple human PDAC patient-derived xenograft models identified peptidyl arginine deiminase 1 (PADI1) as the
top upregulated gene that correlated significantly with poor patient prognosis. Citrullination or deimination of
arginine residues produces a loss of a positive charge, increasing the mass and the acidity of the amino acid
side chain, and the post-translational modification results in altered protein-protein interactions, signaling, and
transcriptional responses. We noted robust expression of PADI1 in human PDAC tumors and cell lines and a
correlation with patient survival. Inhibiting PADI activity or PADI1 knockdown significantly improved the
responsiveness of PDAC cell lines and organoids to components of FOLFIRINOX therapy. PADI1 expressing
PDAC tumors also demonstrated a significant correlation with the glycolytic phenotype and hypoxia gene
signature, showing a reciprocal relationship with oxidative phosphorylation. We also performed an unbiased
CRISPR screen and identified novel metabolic vulnerabilities that may be efficacious for co-targeting with agents
inhibiting PADI1 downstream metabolic pathways. PADI expression also correlated with the reprogramming of
immune and non-immune stroma in the microenvironment. Hence, the proposed project 1 will test the hypothesis
if targeting PADI1 or downstream metabolic reprogramming will abrogate the development of resistance
to FOLFIRINOX in PDAC. We will also investigate the mechanistic basis of stromal remodeling in PDAC
tumors and the stromal reprogramming that contributes to acquired FOLFIRINOX resistance. We propose
three specific aims to test the hypothesis. Aim 1 will investigate the efficacy of targeting PADI1 downstream
pathways and associated mechanisms of stromal remodeling for abrogating resistance to FOLFIRINOX therapy.
Aim 2 will determine the mechanism of tumor-cell intrinsic metabolic reprogramming that also feeds into stromal
reprogramming by PADI1. Aim 3 will investigate the efficacy of targeting the pathways identified in Aims 1 and 2
in PDX models and determine clinical correlates utilizing human tissue specimens. These studies will provide
novel insights and opportunities to target acquired FOLFIRINOX resistance in PDAC.
期刊论文(0)
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会议论文
Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer
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批准号:10518247
-
项目类别:
-
资助金额:$29.39万
-
财政年份:2022
-
负责人:Pankaj Kumar Singh
-
依托单位:
Pancreatic Cancer ARTNet Center
-
批准号:10707504
-
项目类别:
-
资助金额:$126.6万
-
财政年份:2022
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负责人:Pankaj Kumar Singh
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依托单位:
Administrative Core
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批准号:10518244
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项目类别:
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资助金额:$11.83万
-
财政年份:2022
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负责人:Pankaj Kumar Singh
-
依托单位:
Cancer Metabolism Core
-
批准号:10707540
-
项目类别:
-
资助金额:$9.37万
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财政年份:2022
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负责人:Pankaj Kumar Singh
-
依托单位:
Pancreatic Cancer ARTNet Center
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批准号:10518243
-
项目类别:
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资助金额:$128.43万
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财政年份:2022
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负责人:Pankaj Kumar Singh
-
依托单位:
Cancer Metabolism Core
-
批准号:10518246
-
项目类别:
-
资助金额:$9.64万
-
财政年份:2022
-
负责人:Pankaj Kumar Singh
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依托单位:
Administrative Core
-
批准号:10707537
-
项目类别:
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资助金额:$30.72万
-
财政年份:2022
-
负责人:Pankaj Kumar Singh
-
依托单位:
Molecular Basis of ME2-mediated Tumor Suppression in Pancreatic Cancer
-
批准号:10671029
-
项目类别:
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资助金额:$42.2万
-
财政年份:2022
-
负责人:Pankaj Kumar Singh
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依托单位:
Mitochondrial calcium signaling in pancreatic cancer metastasis and progression
-
批准号:10363987
-
项目类别:
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资助金额:$65.54万
-
财政年份:2022
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负责人:Pankaj Kumar Singh
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依托单位:
Mitochondrial calcium signaling in pancreatic cancer metastasis and progression
-
批准号:10565949
-
项目类别:
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资助金额:$62.77万
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财政年份:2022
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负责人:Pankaj Kumar Singh
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依托单位:
Project 3: MUC16-Mediated Metabolic Reprograming Induces PC Metastasis
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批准号:10203864
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项目类别:
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资助金额:$31.64万
-
财政年份:2018
-
负责人:Pankaj Kumar Singh
-
依托单位:
Project 3: MUC16-Mediated Metabolic Reprograming Induces PC Metastasis
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批准号:10413940
-
项目类别:
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资助金额:$31.01万
-
财政年份:2018
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负责人:Pankaj Kumar Singh
-
依托单位:
Metabolic Regulation of Tumor Progression, Metastasis and Chemoresistance by SIRT5/ELK3 signaling in Pancreatic Cancer
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批准号:10662933
-
项目类别:
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资助金额:$0.09万
-
财政年份:2017
-
负责人:Pankaj Kumar Singh
-
依托单位:
Targeting the Metabolic Basis of Cachexia in Pancreatic Cancer
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批准号:10630681
-
项目类别:
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资助金额:$2.0万
-
财政年份:2016
-
负责人:Pankaj Kumar Singh
-
依托单位:
Targeting the Metabolic Basis of Cachexia in Pancreatic Cancer
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批准号:10053712
-
项目类别:
-
资助金额:$43.41万
-
财政年份:2016
-
负责人:Pankaj Kumar Singh
-
依托单位:
Targeting MUC1-induced Tumor-stromal Metabolic Cross-talk in Pancreatic Cancer
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批准号:8370711
-
项目类别:
-
资助金额:$42.86万
-
财政年份:2012
-
负责人:Pankaj Kumar Singh
-
依托单位:
Targeting MUC1-Mediated Tumor-Stromal Metabolic Cross-Talk in Pancreatic Cancer
-
批准号:10738314
-
项目类别:
-
资助金额:$5.48万
-
财政年份:2012
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负责人:Pankaj Kumar Singh
-
依托单位:
Targeting MUC1-Mediated Tumor-Stromal Metabolic Cross-Talk in Pancreatic Cancer
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批准号:10630607
-
项目类别:
-
资助金额:$44.09万
-
财政年份:2012
-
负责人:Pankaj Kumar Singh
-
依托单位:
Targeting MUC1-Mediated Tumor-Stromal Metabolic Cross-Talk in Pancreatic Cancer
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批准号:10679793
-
项目类别:
-
资助金额:$5.48万
-
财政年份:2012
-
负责人:Pankaj Kumar Singh
-
依托单位:
Targeting MUC1-Mediated Tumor-Stromal Metabolic Cross-Talk in Pancreatic Cancer
-
批准号:10684833
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项目类别:
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资助金额:$44.09万
-
财政年份:2012
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负责人:Pankaj Kumar Singh
-
依托单位:
海外基金