ROS-targeted therapy for pancreatic cancer
ROS靶向治疗胰腺癌
基本信息
- 批准号:8963517
- 负责人:
- 金额:$ 46.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:AbraxaneAcute Myelocytic LeukemiaAdenocarcinoma CellAffectAntioxidantsApoptosisBiodistributionCaspaseCell DeathCell LineCell RespirationCellsCharacteristicsClinicalDNA DamageDrug resistanceEngineeringEpithelialEquilibriumFibroblastsGenerationsGenesGenetic TranscriptionGenetically Engineered MouseHumanKRAS2 geneLaboratoriesLeadLibrariesMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMediatingMetabolicMetabolismMitochondriaModelingMusMutateNecrosisNormal CellOncogenicOxidation-ReductionOxidative StressOxygen ConsumptionPancreasPancreatic Ductal AdenocarcinomaPathway interactionsPatientsPhosphorylationPlayPopulationProductionProto-Oncogene Proteins c-aktRadiation therapyReactive Oxygen SpeciesResearch PersonnelResveratrolRoleSafetySeriesSignal TransductionStem cellsTechnologyTestingTherapeutic InterventionToxic effectTransgenic MiceXenograft Modelanalogcancer cellcancer stem cellcancer therapychemotherapydesignextracellulargemcitabinein vivoinnovationmouse modelneoplastic cellnext generation sequencingnovelnovel therapeutic interventionparthenolidepublic health relevanceself-renewalsenescencestemtargeted treatmenttranscription factortumor
项目摘要
DESCRIPTION (provided by applicant): Cancer cells are under persistent oxidative stress. Oncogenic transformation such as with Kras, and metabolic alterations result in increased oxidative stress in tumor cells. Tumor cells adapt to persistent oxidative stress by activating redox sensitive transcription factors that increase the expression of endogenous antioxidants, promote survival pathways, induce chemoresistance, and reduce caspase activation. More significantly, ROS also plays an important role in the survival of cancer stem cells. A subset population of cancer stem cells contains lower ROS levels, thus providing protection against DNA damage such as radiotherapy. Moreover, the self-renewal capacity of cancer stem cells is sensitive to cellular ROS levels. Both bulk tumor and cancer stem cells are vulnerable to excess levels of ROS and this characteristic can be exploited for therapy. Our overarching hypothesis is that compounds able to effectively increase the levels of ROS in cancer cells will tip the balance towards cell death and can potentially overcome drug resistance. Recently, we screened a library of highly diverse compounds on an Extracellular Flux Analyzer that measures cellular respiration. Among hundreds of compounds screened, we identified DFC232, a compound that caused a maximum oxygen consumption rate (OCR) in Mia PaCa-2 cells. DFC232 induced rapid onset of ROS production and activation of AKT, followed by a substantial increase in the phosphorylation of the transcription factor FOXO3a, culminating in cell death. DFC232 shows single agent activity in a Mia PaCa-2 xenograft model with no signs of toxicity. In subsequent mechanistic studies, using a novel next-generation sequencing technology (Bru-Seq), we observed that DFC232 produced a remarkable inactivation of mitochondrial gene transcription by potentially affecting the D-loop. Our first round of ADMET-guided lead optimization campaign generated compounds (e.g. DFC325) with nanomolar potency in a panel of PDAC cell lines and remarkable single agent efficacy in mice. Our central hypothesis is that DFC232 and analogs induce ROS production, tipping the balance toward apoptosis. We further hypothesize that DFCs act through a novel mechanism by effectively disrupting transcription from the mitochondrial D-loop. Moreover, DFC analogs are novel agents with unique targets and have biodistribution, safety, and efficacy characteristics necessary for potential clinical benefit in PDAC treatment. To test our hypothesis we will focus on the following specific aims: Aim 1: To perform ADMET, metabolic, and PK-guided synthesis of novel analogs to enhance potency and efficacy. Aim 2: To perform mechanistic studies of top 5 compounds as single agent and in combination with gemcitabine and abraxane using Bru-Seq technology. Aim 3: To determine the in vivo efficacy of top 5 compounds as single agents and in combination with gem/abraxane in orthotopic and genetically engineered mouse models (GEMM) of KRAS driven pancreatic cancer.
描述(由申请人提供):癌细胞处于持续的氧化应激(例如 Kras)下,代谢改变导致肿瘤细胞通过激活氧化还原敏感转录因子来适应持续的氧化应激。更重要的是,ROS 在癌症干细胞 A 的存活中也发挥着重要作用。癌症干细胞亚群含有较低的 ROS 水平,从而提供针对放射治疗等 DNA 损伤的保护,此外,肿瘤干细胞的自我更新能力对细胞 ROS 水平敏感。我们的总体假设是,能够有效提高癌细胞中 ROS 水平的化合物将打破细胞死亡的平衡,并有可能克服耐药性。细胞外基质上高度多样化的化合物测量细胞呼吸的通量分析仪。在筛选的数百种化合物中,我们鉴定出了 DFC232,这是一种在 Mia PaCa-2 细胞中引起最大耗氧率 (OCR) 的化合物,DFC232 诱导 ROS 快速产生并激活 AKT。在 Mia PaCa-2 异种移植模型中,转录因子 FOXO3a 的磷酸化显着增加,最终导致细胞死亡。在随后的机制研究中,使用新型下一代测序技术 (Bru-Seq),我们观察到 DFC232 通过潜在影响 D 环而产生显着的线粒体基因转录失活。引导先导优化活动产生的化合物(例如 DFC325)在一组 PDAC 细胞系中具有纳摩尔效力,并且在小鼠中具有显着的单药功效。我们的中心假设是 DFC232 和类似物诱导。 ROS 的产生,使平衡向细胞凋亡倾斜。此外,DFC 类似物是具有独特靶点的新型药物,具有生物分布、安全性和功效特性。为了检验我们的假设,我们将重点关注以下具体目标: 目标 1:进行新型类似物的 ADMET、代谢和 PK 指导合成,以增强效力和功效。 2:使用 Bru-Seq 技术对前 5 种化合物作为单药以及与吉西他滨和 abraxane 组合进行机理研究 目标 3:确定前 5 种化合物作为单药以及与 gem/abraxane 组合的体内功效。 KRAS 驱动的胰腺癌的原位和基因工程小鼠模型 (GEMM)。
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(1)
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NOURI NEAMATI其他文献
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