Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy using multi-targeted combinations
Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy using multi-targeted combinations
批准号:
10356147
负责人:
Melissa L Fishel
金额:
$48.39万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
未结题
起止时间:
2013-01-01 至 2025-02-28
关键词:
3-DimensionalAffectBiological ModelsCell DeathCell physiologyCellsChemosensitizationClinicalClinical TrialsCoculture TechniquesCombined Modality TherapyCritical PathwaysDataDevelopmentDiseaseDrug ScreeningDrug TargetingEventExpression ProfilingFDA approvedFibroblastsFundingGenerationsGeneticGenetically Engineered MouseGoalsGrantHeterogeneityHumanHypoxiaIn VitroIndividualLibrariesMalignant NeoplasmsMalignant neoplasm of pancreasMediatingModelingMolecularMolecular TargetOralOxidation-ReductionPancreatic Ductal AdenocarcinomaPathway AnalysisPathway interactionsPatientsPharmaceutical PreparationsPhasePhase Ib TrialPhase Ib/II TrialPhysiologicalProteinsResistanceRoleSTAT3 geneSafetySamplingSignal PathwaySpeedTestingTranscription Factor AP-1Tumor-DerivedWorkbasecancer clinical trialcancer drug resistancecancer survivalcancer therapycarbonate dehydratasecell growthcell killingcell stromachemotherapycomputational pipelinesgemcitabinehypoxia inducible factor 1in vivo Modelinhibitorknock-downmolecular targeted therapiesmortalitymutantnovelnovel strategiesnovel therapeutic interventionpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpre-clinicalprotein expressionresistance mechanismresponsescreeningsingle-cell RNA sequencingstandard of caresynergismsynthetic drugtargeted agenttargeted treatmenttranscription factortranscriptomicstranslational potentialtumortumor growthtumor microenvironment
中文摘要
胰腺导管腺癌(Pancreatic ductal adencarcinoma, PDAC)是一种致命的疾病,5年死亡率约为93%
英文摘要
Pancreatic ductal adenocarcinoma or PDAC is a lethal disease with a 5 year mortality rate of ~93% and little
improvement has been made despite the emergence of several targeted, selective agents. Therefore, a new
approach is needed. We will pursue transcriptomic-guided combination therapy as well as targets that are
upstream of several signaling pathways, thereby affecting multiple downstream cellular processes and potential
resistance mechanisms. Redox factor-1 (Ref-1) is one such protein, as Ref-1 regulates multiple transcriptional
factors (TFs) that are critical to pancreatic cancer survival and drug resistance. In the previous funding period,
we have advanced APX3330, a Ref-1 inhibitor and the first drug targeting Ref-1 to cancer clinical trials (IND
125360) as a novel, oral, first-in-class drug in humans. We have shown that APX3330 reduces tumor growth
in several models of PDAC as a single agent and potentiates gemcitabine-mediated inhibition of cell growth. The
mechanism of action of APX3330 has been extensively investigated and characterized by our team. Through
inhibition of Ref-1, the activity of STAT3, AP-1, NFkB, and HIF-1 can be blocked leading to a decrease in
survival protein expression and response to hypoxia. Recognizing that combination therapy will be necessary in
PDAC, we propose to utilize transcriptomic data to identify FDA-approved agents that are likely to synergize with
APX3330. Drug synthetic lethality is defined as combination therapy of molecular targets whose dual inhibition
leads to potentiation of cell death much more dramatically than when administered as single agents. Single cell
RNA-seq data identified HIF-1 signaling pathways as significantly down-regulated following Ref-1 knockdown
(p=0.0008). Therefore, we tested the combination of Ref-1 inhibition and HIF-1 target, carbonic anhydrase (CA9)
in our 3-Dimensional (3D) tumor co-culture model. Dramatic enhancement of Ref-1-induced cell killing is
observed upon dual-targeting of Ref-1 and CA9. Our hypothesis is that in order to extend the survival of PDAC
patients multi-targeted, combination therapy is essential; therefore we will use original, pathway-driven
screening approaches to discover appropriate FDA approved agents to partner with our Ref-1 inhibitor. AIM 1-
Evaluate the mechanism and efficacy of simultaneous inhibition of the Ref-1 and HIF-1 pathways using in vivo
models of PDAC. AIM 2- Investigate the role of Ref-1 in sensitizing PDAC to chemotherapy currently used in
PDAC treatment. Gemcitabine (Gem), one of the agents that single cell RNA-seq expression profiling predicted
should work with APX3330, will be used in combination with APX3330 in the phase 1B trial. AIM 3- Screen for
drug synthetic lethal hits following Ref-1 inhibition in a validated 3D model system utilizing computational and
transcriptomics pathway analysis. Selective disruption of individual molecular effectors has clear limitations; our
approach focuses on multi-targeted combination treatments. Thus, this project has the potential to extend
pancreatic cancer survival by using appropriate disease-relevant models such as 3D co-culture spheroids,
orthotopic, and GEM models.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
Metabolic flux analysis and PDX models to understand therapeutic vulnerabilities following inhibition of Ref-1 redox signaling in pancreatic cancer
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批准号:10717281
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项目类别:
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资助金额:$46.63万
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财政年份:2023
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负责人:Melissa L Fishel
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依托单位:
Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors
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批准号:10629287
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项目类别:
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资助金额:$42.48万
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财政年份:2021
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负责人:Melissa L Fishel
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依托单位:
Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors
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批准号:10415004
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项目类别:
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资助金额:$42.48万
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财政年份:2021
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负责人:Melissa L Fishel
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依托单位:
Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors
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批准号:10297976
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项目类别:
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资助金额:$44.81万
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财政年份:2021
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负责人:Melissa L Fishel
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依托单位:
Novel Role of Ref-1 in Pancreatic Cancer Etiology and Progression
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批准号:8601527
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项目类别:
-
资助金额:$47.91万
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财政年份:2013
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负责人:Melissa L Fishel
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依托单位:
Novel Role of Ref-1 in Pancreatic Cancer Etiology and Progression
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批准号:9195076
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项目类别:
-
资助金额:$49.4万
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财政年份:2013
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负责人:Melissa L Fishel
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依托单位:
Novel Role of Ref-1 in Pancreatic Cancer Etiology and Progression
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批准号:8449854
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项目类别:
-
资助金额:$49.4万
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财政年份:2013
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负责人:Melissa L Fishel
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依托单位:
Chemosensitization of Pancreatic Tumors via Inhibition of a DNA BER Enzyme, Ape1
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批准号:7254589
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项目类别:
-
资助金额:$15.15万
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财政年份:2007
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负责人:Melissa L Fishel
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依托单位:
Chemosensitization of Pancreatic Tumors via Inhibition of a DNA BER Enzyme, Ape1
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批准号:7414742
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项目类别:
-
资助金额:$18.18万
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财政年份:2007
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负责人:Melissa L Fishel
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依托单位:
海外基金