PIK3CA signaling and pancreatic cancer
PIK3CA 信号传导与胰腺癌
基本信息
- 批准号:10722155
- 负责人:
- 金额:$ 22.06万
- 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:2023-07-08 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAnimalsAntibodiesCancer EtiologyCell LineCellsCellular Metabolic ProcessCessation of lifeClinicalClinical TrialsDataDiseaseEnvironmentExhibitsExposure toFDA approvedFlow CytometryGene DeletionGenesGeneticGoalsGrowthHarvestHistocompatibility Antigens Class IHumanHyperlipidemiaHypoxiaImmune EvasionImmune checkpoint inhibitorImmune responseImmune systemImmunocompetentImmunohistochemistryImmunologicsImmunosuppressionImmunotherapeutic agentImmunotherapyImplantInfiltrationKPC modelKRAS oncogenesisKRAS2 geneKRASG12DLaboratoriesLeucocytic infiltrateMHC Class I GenesMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMediatingMetabolicMusMutationNamesOncogenicOperative Surgical ProceduresPIK3CA genePancreasPancreatic Ductal AdenocarcinomaPathway interactionsPharmaceutical PreparationsPharmacological TreatmentPharmacotherapyPilot ProjectsPlayProteinsRNAReportingResistanceRoleSCID MiceSignal TransductionT cell infiltrationT cell therapyT-Cell ReceptorT-LymphocyteTarget PopulationsTestingTherapeuticTherapeutic StudiesTreatment ProtocolsUp-RegulationWorkalpelisibanti-PD-1anti-PD1 antibodiescancer cellcancer infiltrating T cellscarboxylatecarboxylationcell typeeffective therapyefficacy testingexhaustionexperimental studygenome-wideimmune checkpointimmune clearanceimplantationimprovedin vivo imaging systemin vivo monitoringinhibitorinstrumentmetabolic profilemethylmalonyl-coenzyme Amouse modelneoplastic cellneutralizing antibodypancreatic cancer cellspancreatic neoplasmpharmacologicprogrammed cell death ligand 1programmed cell death protein 1propionyl-coenzyme Aside effectsingle cell sequencingtherapeutic targettumortumor growthtumor progressiontumor-immune system interactions
项目摘要
The goal of this proposal is to explore how to target PIK3CA signaling for treatment of pancreatic ductal
adenocarcinoma (PDAC). This deadly cancer is highly resistant to current treatment regimens, including
immunotherapy with checkpoint inhibitors. More than 90% of PDAC have oncogenic mutations in KRAS, and
PIK3CA is a direct effector of KRAS. Our group first reported that genetic ablation of PIK3CA in the pancreas
completely protected mice against oncogenic KRAS-induced tumor formation, and subsequently reported that
PIK3CA plays a critical role in sustaining pancreatic tumors by shielding them from the immune system.
Orthotopic implantation of KrasG12D;Trp53R172H;Pdx1-Cre (KPC) pancreatic tumor cells in immunocompetent
mice caused 100% lethality, whereas mice implanted with Pik3ca-/- KPC (PIK3CA-KO) KPC cells exhibited
tumor regression with 100% animal survival. A genome-wide gene deletion screen to search for molecules that
can reverse the elimination of PIK3CA-KO cells by the immune system identified PCCB, which catalyzes the
carboxylation of propionyl-CoA to produce methylmalonyl-CoA. PCCB-null PIK3CA-KO KPC cells were
generated, and when implanted in mice, these tumors were not cleared by the host immune system. Two
hypotheses will be tested: 1) Oncogenic KRAS activation of PIK3CA modulates a PCCB-regulated metabolic
environment that favors evasion of pancreatic cancer from immune elimination; and 2) Alpelisib inhibition of
PIK3CA enhances the activity of anti-PD1 plus anti-PCSK9 therapy against pancreatic tumors. Aim 1
investigates mechanisms by which KRAS activation of PIK3CA modulates a PCCB-regulated metabolic
environment that favors immune evasion of pancreatic cancer, including upregulation of immune checkpoints
and T cell exhaustion. Tumor infiltrating T cells will be isolated and analyzed by single-cell RNA and T cell
receptor (TCR) V(D)J sequencing, flow cytometry and IHC. Adoptive T cell transfer experiments will be
performed to determine if T cells previously exposed to PCCB-null PIK3CA-KO tumors will eliminate PIK3CA-
KO tumors implanted in SCID mice. Cell metabolism and immunological profile of PCCB-null PIK3CA-KO vs.
PIK3CA-KO and parental KPC cell lines will be measured to better understand the metabolic alterations
controlled by PIK3CA and PCCB and how these changes may lead to immune suppression. Aim 2 is a
therapeutic study that tests the efficacy of alpelisib, a PIK3CA inhibitor, in combination with neutralizing
antibodies against PD-1 and PCSK9 for treatment of pancreatic cancer using the orthotopically implanted KPC
mouse model. Tumor infiltrating T cells will also be isolated and analyzed by single-cell sequencing. In
summary, this proposal will investigate how PIK3CA signaling regulates the metabolic and immunological
profile of pancreatic cancer. Alpelisib, anti-PD1 antibodies and anti-PCSK9 antibodies are all FDA-approved for
clinical use. Successful completion of our studies may lead to clinical trials with these approved drugs for
treatment of pancreatic cancer.
本提案的目的是探索如何靶向PIK3CA信号治疗胰管
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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RICHARD Z LIN其他文献
RICHARD Z LIN的其他文献
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{{ truncateString('RICHARD Z LIN', 18)}}的其他基金
The role of PI3K in pancreatic cancer genetics and progression
PI3K 在胰腺癌遗传学和进展中的作用
- 批准号:
10266023 - 财政年份:2018
- 资助金额:
$ 22.06万 - 项目类别:
PI3K signaling and channelopathies in the heart
心脏中的 PI3K 信号传导和通道病
- 批准号:
9295021 - 财政年份:2016
- 资助金额:
$ 22.06万 - 项目类别:
Mouse model to study dependence of pancreatic cancer on Pik3ca for progression
研究胰腺癌对 Pik3ca 进展依赖性的小鼠模型
- 批准号:
9188056 - 财政年份:2015
- 资助金额:
$ 22.06万 - 项目类别:
Decreased PI3K Signaling and Long QT Syndrome in Diabetes
糖尿病患者 PI3K 信号传导减弱和长 QT 综合征
- 批准号:
8762239 - 财政年份:2013
- 资助金额:
$ 22.06万 - 项目类别:
Decreased PI3K Signaling and Long QT Syndrome in Diabetes
糖尿病患者 PI3K 信号传导减弱和长 QT 综合征
- 批准号:
8544539 - 财政年份:2013
- 资助金额:
$ 22.06万 - 项目类别:
Decreased PI3K Signaling and Long QT Syndrome in Diabetes
糖尿病患者 PI3K 信号传导减弱和长 QT 综合征
- 批准号:
8966666 - 财政年份:2013
- 资助金额:
$ 22.06万 - 项目类别:
Gq-coupled Receptors Inhibit PI 3-kinase/Akt Signaling Pathway
Gq 偶联受体抑制 PI 3 激酶/Akt 信号通路
- 批准号:
8003647 - 财政年份:2009
- 资助金额:
$ 22.06万 - 项目类别:
Gq-coupled Receptors Inhibit PI 3-kinase/Akt Signaling Pathway
Gq 偶联受体抑制 PI 3 激酶/Akt 信号通路
- 批准号:
7525551 - 财政年份:2002
- 资助金额:
$ 22.06万 - 项目类别:
Gq-coupled Receptors Inhibit PI 3-kinase/Akt Signaling Pathway
Gq 偶联受体抑制 PI 3 激酶/Akt 信号通路
- 批准号:
7645586 - 财政年份:2002
- 资助金额:
$ 22.06万 - 项目类别:
Gq-Coupled Receptors Inhibit PI 3-Kinase/Akt Signaling Pathway
Gq 偶联受体抑制 PI 3 激酶/Akt 信号通路
- 批准号:
8064263 - 财政年份:2002
- 资助金额:
$ 22.06万 - 项目类别:
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