Targeting Cell Cycle Plasticity in Pancreatic Ductal Adenocarcinoma
靶向胰腺导管腺癌的细胞周期可塑性
基本信息
- 批准号:10044497
- 负责人:
- 金额:$ 43.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAnimal Cancer ModelAnimalsApoptosisAutomobile DrivingBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast Cancer cell lineCDC2 geneCDK2 geneCDK4 geneCDKN2A geneCell CycleCell Cycle ProteinsCell DeathCell LineCell ProliferationCellsClinicClinicalCyclin D1DataDependenceDevelopmentDiseaseDoxycyclineDrug Delivery SystemsEarly DiagnosisEngineeringEpigenetic ProcessEstrogen receptor positiveFinancial compensationFormulationGenesGeneticGoalsIn VitroInjectionsKRAS2 geneLeadLiposomesMalignant NeoplasmsMammary NeoplasmsMediatingMetastatic breast cancerModalityModelingMolecular ConformationMutationNecrosisOperative Surgical ProceduresOralPancreatic Ductal AdenocarcinomaPatient-Focused OutcomesPatientsPeptidesPhosphorylationPhosphotransferasesProgression-Free SurvivalsProtein Tyrosine KinaseRefractoryResistanceSignal PathwaySignal TransductionSurvival RateTailTestingTherapeutic EffectToxic effectTranslatingTumor VolumeTyrosineVeinsWorkXenograft Modelbasecell growthclinically relevantin vivoin vivo Modelinducible gene expressioninhibitor/antagonistmalignant breast neoplasmmouse modelmutational statusneoplastic cellnovelnovel strategiespeptide drugpreventprotein expressionresponsesenescencesmall molecule inhibitortargeted treatmenttherapeutic targettranscriptometumortumor progression
项目摘要
There is an urgent unmet need to develop targeted therapeutic options for Pancreatic Ductal Adenocarcinoma
(PDAC), which continues to be a therapy recalcitrant disease. Data has shown that perturbation of two specific
genes, K-Ras and CDKN2A, are nearly universal in PDAC. Based on this mutational profile, PDAC was
thought initially to be a good candidate for CDK4 inhibition therapy. However, most PDAC cell lines and PDX
models are resistant and this appears to be due to the activation of another kinase CDK2. The CDK4/6 specific
inhibitors (CDK4i) are approved for metastatic HR+ breast cancer. However, while CDK4i therapy initially
increases progression-free survival in ER+ metastatic breast cancer (BC) patients, ultimately the majority
develop secondary resistance, due to compensation by CDK2. Thus, both CDK4i-refractory breast cancer and
PDAC appear resistant by the same mechanism. Therefore, to generate a better inhibitor for metastatic breast
cancer patients and PDAC, one needs to inhibit both the kinase driving cancer (CDK4/6) and the kinase
causing resistance (CDK2). CDK2 small molecule inhibitors also target the highly conserved and essential
CDK1 kinase and have met with unacceptable toxicity in the clinic, so this approach has proven unsuccessful.
In this exploratory R21 application, we propose using a novel strategy. Instead of targeting the conserved
active sites of CDK4/6 and CDK2, we target p27Kip1, which is a CDK assembly factor and CDK ON/OFF
switch. Tyrosine (Y) phosphorylation of p27 (pY88) by the tyrosine kinase Breast tumor Related Kinase (Brk)
causes a conformational change in p27 bound to CDKs, turning them “ON”. We demonstrated that in breast
cancer cells blocking phosphorylation of p27 with the therapeutic peptide ALT inactivated CDK4/6 and CDK2
and represented a new way to block ER+ BC cell proliferation, induce senescence and ultimately cause cell
death, which translates into tumor regression and increased OS in BC animal models. We have shown that
p27 is Y phosphorylated in several established PDAC cell lines, and expression of ALT in two cell lines
inhibited proliferation, suggesting that CDK2 might be inhibited by ALT-mediated targeting of p27 in PDAC.
Our hypothesis is that inhibition of CDK4/6 and CDK2 by the therapeutic peptide ALT will block proliferation of
PDAC and represents a novel way to target this tumor type. Our specific Aims: 1) To examine the effect
that ALT and pY blockage therapy has on PDAC cell lines in vitro. 2) To examine the therapeutic effect
pY blockage therapy and ALT in vivo in PDAC mouse models. A panel of primary patient derived Cell
(PDC) lines, which have been sequenced and characterized, and cross-matched PDX models will be used to
test ALT's effect on cell growth and tumor progression. ALT will be delivered by two modes: inducible
expression and a novel liposomal-peptide formulation. This exploratory R21 project will test the hypothesis that
targeting p27 in clinically relevant in vitro and in vivo models, as a proof of concept approach, may represent a
viable clinical strategy, which should be further explored.
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胰导管腺癌迫切需要开发有针对性的治疗方案
项目成果
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Chongmin Huan其他文献
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