Therapeutic potential of Palmatine in pancreatic cancer
Therapeutic potential of Palmatine in pancreatic cancer
批准号:
9348827
负责人:
ADDANKI PRATAP KUMAR
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-07-01 至 2021-06-30
关键词:
AbraxaneAddressAdverse effectsAnimal ModelAnimalsBiochemicalBiological AssayCOL1A1 geneCancer EtiologyCancer PatientCell CommunicationCell Culture TechniquesCellsCessation of lifeClinical ManagementCoculture TechniquesColonColorectal CancerCommunicationConditioned Culture MediaCytotoxic ChemotherapyDesmoplasticDevelopmentDiagnosisDiseaseEnvironmentEvaluationExtracellular MatrixExtracellular SpaceFibrosisFluorouracilGenesGeneticGoalsGrowthHumanIn VitroIncidenceInflammationInstitutionInterventionInvestigationKRAS2 geneKnowledgeLaboratoriesLeucovorinLungMaintenanceMalignant NeoplasmsMalignant neoplasm of pancreasMalignant neoplasm of prostateMechanicsMediatingMusNeoplasm MetastasisNeutropeniaNew AgentsOncogenicOncologistPaclitaxelPancreasPancreatic Ductal AdenocarcinomaPathogenesisPatientsPeripheral Nervous System DiseasesPharmaceutical PreparationsPharmacologyPhellodendronPlayProductionPrognostic MarkerPulmonary InflammationRegimenRoleSHH geneSeminalSerumStromal NeoplasmTestingTherapeuticThrombocytopeniaTissue ModelTissuesToxic effectTransgenic ModelTreatment EfficacyTreatment Protocolsbasecancer cellchemotherapeutic agentchemotherapyclinical careclinical practiceclinical translationcostearly detection biomarkersgemcitabinehydrophilicityin vivoinnovationirinotecanmalignant breast neoplasmmolecular markermortalitynovel therapeutic interventionoxaliplatinpancreatic cancer cellspancreatic neoplasmparacrinepre-clinicalstandard of carestellate celltherapeutic developmenttherapy resistanttranscription factortreatment strategytumortumor microenvironment
中文摘要
目前预测胰腺导管腺癌(PDAC)将成为第二大病因
英文摘要
Current projections predict pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause
of cancer-related deaths surpassing breast, prostate and colorectal cancers by 2030. Lack of treatment
strategies that can reduce the near equal incidence and mortality rate is a barrier for this disease. A key
feature of PDAC is desmoplasia, which is characterized by increased fibrosis and inflammation. Desmoplasia
plays a critical role not only in pancreas pathogenesis but also in tumor maintenance and limiting therapeutic
efficacy by decreasing drug access to the tumor. Pancreatic stellate cells (PSCs) present in the tumor
microenvironment (TME) are major contributors to desmoplasia. Accordingly, targeting tumor-stromal
interactions by reprogramming PSC activation has emerged as a new therapeutic strategy and led to drugs
such as Nab-Paclitaxel in combination with Gemcitabine. However their utility have been limited. Therefore, we
propose that in addition to “reprogramming PSC activation” disruption of PSC interaction with pancreatic
cancer cells (PCCs) is critical for effective PDAC inhibition. We have identified a new compound (Palmatine;
PMT) that shows preliminary evidence of fitting this paradigm. We have hypothesized that “PMT-mediated
inhibition of sonic hedgehog (Shh) from PCCs that mediates activation of GLI/COL1A1 axis in PSCs and
releases COL1A1 into the TME will disrupt activation of PSC as well as its interaction with PCCs to inhibit
fibrosis associated with desmoplasia”. This hypothesis will be tested using relevant cell culture and preclinical
animal models in three specific aims. Aim 1 studies will test the hypothesis that activation of Shh from PCCs
leads to activation of GLI/COL1A1 axis in PSCs and subsequent release of COL1A1 into the extracellular
space to facilitate interaction with PCCs and PMT will inhibit this paracrine interaction. Pharmacological,
genetic inhibition and rescue approaches will be combined with biochemical and functional assays to address
these studies in co-culture and conditioned media culture conditions. Aim 2 studies will test the hypothesis
that PMT disrupts paracrine interaction between PCC-PSC in vivo to suppress PDAC development using the
pre-clinical LSL K-ras G12D+; LSL-Trp53R172H/+; Pdx-1Cre transgenic model (KPC mice). Histopathological
evaluation of pancreas including tumor grade and metastasis, tissue levels of molecular markers, tissue and
serum levels of PMT and serum metabolite alterations will be assessed. Aim 3 studies test the hypothesis
that PMT will inhibit GLI, COL1A1, in short-term ex vivo cultures of patient-derived pancreatic tissues.
Impact of the study: This paradigm changing study will establish the notion that targeting the activation of
PSC and inhibiting its interaction with PCC is required to provide therapeutic efficacy for PDAC. Pancreatic
cancer patient tissues will provide evidence of the usefulness of PMT against human PDAC; and set the stage
for clinical translation. Further this study will also identify molecules that can be developed as markers to
predict therapeutic resistance/sensitivity, which will also have significant translational potential.
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