Sensitization to Chemoradiation by Therapeutic Targeting of the DNA Damage Response
通过 DNA 损伤反应的治疗靶向来提高放化疗敏感性
基本信息
- 批准号:9901492
- 负责人:
- 金额:$ 58.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:ApoptoticBiological AssayBiological MarkersBody Weight decreasedCASP3 geneCancer Therapy Evaluation ProgramCell Cycle CheckpointCell DeathCell LineCell SurvivalCell modelCellsCellular AssayCharacteristicsClinical TrialsCollectionCombined Modality TherapyComet AssayDNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA biosynthesisDataDefectDependenceDominant Genetic ConditionsDoseDose-LimitingDouble Strand Break RepairDrug TargetingFutureGerm CellsGoalsGoldImageImmune systemImmunocompetentInvestigationMagnetic Resonance ImagingMalignant neoplasm of pancreasMeasuresMutationNonhomologous DNA End JoiningNormal CellNormal tissue morphologyOrganPRKDC genePancreatic Ductal AdenocarcinomaPathway interactionsPatientsPhosphotransferasesRadiationRadiation ToleranceReporterSafetyScheduleSmall IntestinesSurrogate MarkersTP53 geneTherapeutic IndexTimeToxic effectTranslatingTreatment EfficacyTumor MarkersValidationXenograft procedureadvanced pancreatic cancerbasecellular targetingchemoradiationchemotherapyclinical developmentdesigndiffusion weightedefficacy studygastrointestinalgemcitabinehigh throughput screeninghuman modelimaging biomarkerimprovedimproved outcomein vivoinhibitor/antagonistintestinal cryptmouse modelneoplastic cellpancreatic cancer cellspancreatic neoplasmpharmacodynamic biomarkerpre-clinicalpredictive markerpreventresponseresponse biomarkerstandard of caretargeted agenttargeted biomarkertargeted sequencingtherapeutic targettissue injurytreatment responsetumortumor growth
项目摘要
ABSTRACT
There is an urgent need to improve the efficacy of chemoradiation therapy for patients with locally advanced
pancreatic cancer (LAPC). Since unrepaired DNA double-strand breaks (DSB) are responsible for the majority
of cell death in response to chemoradiation, targeting cellular DNA damage response (DDR) pathways is a
promising approach to enhance the efficacy of chemoradiation therapy by preventing efficient repair of DNA
damage, leading to loss of tumor cell viability. Since defects in the DDR such as P53 mutation occur in up to
70% of pancreatic ductal adenocarcinomas (PDAC), targeted inhibition of the DDR provides an opportunity to
selectively enhance sensitivity to chemoradiation in tumor but not normal cells. The overall goal of our
proposed study is to identify agents from the CTEP collection that modulate the cellular response to
DNA damage and best sensitize tumor cells to standard of care chemoradiation therapy. To achieve this
goal, we will in Aim 1 conduct an unbiased high throughput screen (HTS) in a panel of PDAC cell lines using a
panel of agents from the CTEP collection that modulate the cellular DDR, including drugs that target ATR,
DNAPK, PARP, and WEE1 (Aim 1A). An initial cell viability screen at various concentrations of single agents
alone or in combination with chemoradiation will be conducted. In addition to concentration, optimal
sequencing of targeted agents with chemoradiation will be investigated. A live cell assay for the DDR as well
as apoptotic cell death will be utilized as orthogonal screens to assist in hit prioritization and validation. In Aim
1B, a group of agents selected by defined criteria will be further evaluated by conducting a “gold standard”
clonogenic survival assay using a panel of PDAC cell lines. In Aim 1C we will conduct a normal cell counter
screen using the above agents against normal cells to identify those which cause toxicity in combination with
chemoradiation. The efficacy of these prioritized agents will be validated in Aim 1D using a panel of patient-
derived xenograft (PDX) sphere explant cultures. Two agents with the optimal enhancement ratio (1B and 1D),
and safety (1C) at the optimal concentration and schedule (1A and 1B) will be studied in Aim 2. We will
compare the therapeutic efficacy of the nominated agents in combination with chemoradiation using both PDX
and immune competent syngeneic mouse models of PDAC (Aim 2A). Normal tissue injury caused by these
two agents (Aim 2B) will be evaluated, which together with tumor efficacy will lead to the choice of the agent to
pursue in clinical trials. Aim 3 will delineate the mechanistic basis for the chemoradiation potentiating activity of
the superior agent (Aim 3A) with the goal of selecting pharmacodynamic and imaging biomarkers (Aims 3B
and 3C), using in vivo studies in mouse models, for the future clinical trial. Completion of these aims will
provide the required preclinical data regarding efficacy, safety, and biomarkers of response (mechanistic- and
imaging- based) for the rationale design of a future clinical trial for patients with LAPC.
抽象的
迫切需要提高局部晚期患者放化疗的疗效
胰腺癌(LAPC)。由于未修复的 DNA 双链断裂 (DSB) 是造成大多数
细胞因放化疗而死亡,靶向细胞 DNA 损伤反应 (DDR) 途径是一种
通过阻止 DNA 的有效修复来增强放化疗疗效的有前途的方法
损伤,导致肿瘤细胞活力丧失。由于 DDR 中的缺陷(例如 P53 突变)最多发生在
70% 的胰腺导管腺癌 (PDAC),靶向抑制 DDR 提供了机会
选择性增强肿瘤细胞而非正常细胞对放化疗的敏感性。我们的总体目标
拟议的研究是从 CTEP 集合中识别调节细胞反应的药物
DNA 损伤并使肿瘤细胞对标准放化疗更加敏感。为了实现这一目标
为了实现目标,我们将在目标 1 中使用 PDAC 细胞系面板进行无偏高通量筛选 (HTS)
CTEP 系列中调节细胞 DDR 的一组药物,包括针对 ATR 的药物,
DNAPK、PARP 和 WEE1(目标 1A)。不同浓度单一试剂的初始细胞活力筛选
单独进行或与放化疗联合进行。除了浓度之外,最佳
将研究放化疗靶向药物的测序。 DDR 的活细胞检测
因为凋亡细胞死亡将被用作正交筛选,以协助命中优先级排序和验证。瞄准
1B,根据定义的标准选择的一组代理将通过执行“黄金标准”进一步评估
使用一组 PDAC 细胞系进行克隆存活测定。在目标 1C 中,我们将进行正常的细胞计数
使用上述药物针对正常细胞进行筛选,以识别那些与以下药物组合引起毒性的药物:
放化疗。这些优先药物的功效将在 Aim 1D 中使用一组患者进行验证
衍生异种移植(PDX)球体外植体培养物。具有最佳增强比例的两种药剂(1B 和 1D),
目标 2 将研究最佳浓度和时间表(1A 和 1B)下的安全性(1C)。我们将
使用 PDX 比较提名药物与放化疗联合的治疗效果
和具有免疫能力的 PDAC 同系小鼠模型(目标 2A)。这些引起的正常组织损伤
将评估两种药物(目标 2B),这与肿瘤疗效一起将导致药物的选择
追求临床试验。目标 3 将描述放化疗增强活性的机制基础
优质药物(目标 3A),目标是选择药效学和成像生物标志物(目标 3B)
和3C),使用小鼠模型的体内研究,用于未来的临床试验。完成这些目标将
提供有关功效、安全性和反应生物标志物(机械和机制)所需的临床前数据
基于成像)为 LAPC 患者未来临床试验的基本原理设计。
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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THEODORE S LAWRENCE其他文献
THEODORE S LAWRENCE的其他文献
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{{ truncateString('THEODORE S LAWRENCE', 18)}}的其他基金
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局部晚期癌症的分子靶向放射增敏
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Targeting Stromal Influences on BCKA Addiction in PDAC Tumors
靶向基质对 PDAC 肿瘤 BCKA 成瘾的影响
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10581670 - 财政年份:2022
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7893334 - 财政年份:2010
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