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.
摘要
项目成果
期刊论文数量(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
Molecularly Targeted Radiosensitization of Locally Advanced Cancers
局部晚期癌症的分子靶向放射增敏
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10554470 - 财政年份:2023
- 资助金额:
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Targeting Stromal Influences on BCKA Addiction in PDAC Tumors
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$ 58.21万 - 项目类别:
Targeting Stromal Influences on BCKA Addiction in PDAC Tumors
靶向基质对 PDAC 肿瘤 BCKA 成瘾的影响
- 批准号:
10581670 - 财政年份:2022
- 资助金额:
$ 58.21万 - 项目类别:
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Development of a first-in-class mEGFR dimerization inhibitor
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10435117 - 财政年份:2020
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10778673 - 财政年份:2020
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$ 58.21万 - 项目类别:
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- 资助金额:
$ 58.21万 - 项目类别:
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7891047 - 财政年份:2010
- 资助金额:
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