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.
!
开发胰腺导管腺癌的靶向治疗方案是一项尚未得到满足的迫切需要
(PDAC),这仍然是一种治疗顽固性疾病。数据表明,两个特定的扰动
K-RAS和CDKN2A基因在PDAC中几乎是普遍存在的。根据这一突变特征,PDAC是
最初被认为是CDK4抑制治疗的良好候选者。然而,大多数PDAC细胞系和PDX
模型是耐药的,这似乎是由于另一种激酶CDK2的激活。CDK4/6特异性
抑制剂(CDK4i)被批准用于转移性HR+乳腺癌。然而,虽然CDK4i最初的治疗
提高ER+转移性乳腺癌(BC)患者的无进展生存率,最终大多数
由于CDK2的补偿,产生二次抗性。因此,CDK4i-难治性乳腺癌和
PDAC通过同样的机制表现出抗药性。因此,为了产生一种更好的转移性乳腺抑制物
癌症患者和PDAC,需要同时抑制驱动癌症的激酶(CDK4/6)和激酶
引起抗性(CDK2)。CDK2小分子抑制剂也针对高度保守和必需的
并在临床上遇到了不可接受的毒性,因此这种方法被证明是不成功的。
在这个探索性的R21应用中,我们建议使用一种新的策略。与其把目标对准保守的
CDK4/6和CDK2的活性位点,我们针对的是CDK组装因子p27Kip1和CDK开/关
换一下。酪氨酸激酶乳腺肿瘤相关蛋白(BRK)对p27(PY88)的酪氨酸(Y)磷酸化
导致与CDK结合的p27的构象变化,使它们“开启”。我们在乳房中证明了这一点
肿瘤细胞用ALT失活的CDK4/6和CDK2阻断p27的磷酸化
为阻断ER+BC细胞增殖,诱导衰老,最终导致细胞死亡提供了一条新途径
死亡,在BC动物模型中转化为肿瘤消退和OS增加。我们已经证明了
P27在几个已建立的PDAC细胞系中是Y磷酸化的,在两个细胞系中ALT的表达
抑制增殖,提示CDK2可能通过ALT介导的p27靶向在PDAC中被抑制。
我们的假设是,治疗性多肽ALT抑制CDK4/6和CDK2将阻断细胞的增殖。
PDAC,代表了一种新的靶向这种肿瘤类型的方法。我们的具体目标是:1)检查效果
ALT和Py阻断治疗对体外培养的PDAC细胞的影响。2)检查治疗效果
PY阻断治疗和体内ALT在PDAC小鼠模型中的作用。一组原发患者来源的细胞
(PDC)线,已排序和表征,以及交叉匹配的PDX模型将用于
检测丙氨酸氨基转移酶对细胞生长和肿瘤进展的影响。ALT将通过两种模式提供:诱导式
表达和一种新的脂质体-多肽制剂。这个探索性的R21项目将检验这样的假设
作为一种概念验证方法,在临床相关的体外和体内模型中靶向p27可能代表着一种
可行的临床策略,应进一步探索。
好了!
项目成果
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