Novel DNA damage response therapeutics targeting replication protein A
针对复制蛋白 A 的新型 DNA 损伤反应疗法
基本信息
- 批准号:10432115
- 负责人:
- 金额:$ 49.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAutomobile DrivingBiochemicalCHEK1 geneCHEK2 geneCRISPR screenCell DeathCellsCharacteristicsChemicalsChromosomal RearrangementChromosomesClinicalClinical TrialsCombined Modality TherapyCoupledDNA BindingDNA DamageDNA Repair PathwayDNA-dependent protein kinaseDataDevelopmental Therapeutics ProgramDrug TargetingEpithelial CellsEpithelial ovarian cancerGeneticGenetic DeterminismGenetic ModelsGenomic DNAHealthHumanIndividualMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMeasuresMethodologyModelingMolecularMutationNon-Small-Cell Lung CarcinomaOncogenicPathway interactionsPatientsPharmacologyPhosphotransferasesPlayPublishingResearchRoleSS DNA BPSeriesSerousSignal TransductionSingle-Stranded DNATherapeuticTherapeutic AgentsToxic effectTumor-Derivedanticancer activityataxia telangiectasia mutated proteincancer cellcancer typechemical geneticsclinically relevantdriver mutationeffective therapyexhaustiongenome sequencinghomologous recombinationin vivoinhibitorinhibitor therapynovelnovel therapeuticspatient derived xenograft modelpatient responsepersonalized medicinerepairedreplication factor Areplication stressresponsesmall moleculesuccesstargeted agenttargeted cancer therapytargeted treatmenttherapeutic targettreatment responsetreatment strategywhole genome
项目摘要
Novel DNA damage response therapeutics targeting replication protein A
Abstract
The DNA damage response (DDR) is now considered a tractable pathway to target for cancer therapy. The
DDR and DNA repair pathways are also amenable to personalized therapies by exploiting synthetic lethal
interactions as evidenced by the clinical success of PARP inhibitors in homologous recombination (HR)
deficient cancers. The DDR is initiated by engagement of the PI3 kinase-related kinases ATM, ATR, and DNA-
PK. These kinases and the downstream checkpoint kinases CHK1 and CHK2, are clinically validated targets
being actively investigated in multiple clinical trials. A novel target in the DDR pathway is the human single
stranded DNA binding protein, replication protein A (RPA) which plays a critical role in the DDR to detect
replication stress (RS) and signal to the ATR kinase. RS is a common feature in cancer cells and provides the
therapeutic window for the anticancer activity of DDR targeted drugs. RS coupled with a DDR blockade results
in replication catastrophe (RC) and eventually cell death. RPA is a critical protector from RC and depletion of
RPA or “RPA exhaustion” can elicit RC and cell death when there is insufficient single-strand DNA binding
capacity to protect the genomic DNA. We have identified a potent and selective small molecule RPA inhibitor
(RPAi), NERx 329, which possesses biochemical RPA inhibition and cellular engagement of RPA. NERx 329
also displays no overt toxicity in vivo and possesses anticancer activity alone and in combination with DNA
damaging chemotherapeutics and certain DDR targeted agents. While the anticancer activity could be the
result of inhibiting RPA’s role in individual repair or replication pathways, our published and preliminary data
point to a more global mechanism of action. Our overarching hypothesis is that chemical inhibition of
RPA can mimic RPA exhaustion to inhibit the DDR and provide selective anticancer activity via novel
genetic interactions common in lung and ovarian cancer. To address this hypothesis, we will elucidate the
mechanisms and determinants of the cellular anticancer activity of our novel RPAi. We will focus on two
cancers types, high grade serous epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC), as
our analysis of clinical survival data reveals an important role for RPA in these cancers. In Aim 1 we will
interrogate how chemical exhaustion of RPA impacts RS and the DDR in lung and ovarian cancer. Aim 2 will
focus on elucidating the genetic determinants of sensitivity to RPAi’s. We will identify novel chemical-genetic
interactions in a DDR focused CRISPR screen assessing RPAi activity. Clinically relevant genetic interactions
will be identified in a unique series of PD-EOC spheroid lines we have developed. Whole genome sequencing
will identify genetic alterations and chromosomal rearrangements which may correlate with response to RPAi
therapy. From these studies, specific genetic alterations that impact RPAi sensitivity will be validated with in
vivo PDX models of lung and ovarian cancer and DDR targeted developmental therapeutic agents. Completion
of these aims will define RPAi mechanism of action and the genetic interactions that dictate RPAi sensitivity.
These data are crucial towards developing novel DDR targeted cancer therapeutics and identifying the relevant
genetics characteristics to maximize patient response and efficacy.
靶向复制蛋白A的新型DNA损伤反应疗法
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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JOHN J. TURCHI其他文献
JOHN J. TURCHI的其他文献
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{{ truncateString('JOHN J. TURCHI', 18)}}的其他基金
Novel DNA damage response therapeutics targeting replication protein A
针对复制蛋白 A 的新型 DNA 损伤反应疗法
- 批准号:
10317276 - 财政年份:2021
- 资助金额:
$ 49.69万 - 项目类别:
Novel DNA damage response therapeutics targeting replication protein A
针对复制蛋白 A 的新型 DNA 损伤反应疗法
- 批准号:
10653707 - 财政年份:2021
- 资助金额:
$ 49.69万 - 项目类别:
Targeting nucleotide excision repair in combination cancer therapy
联合癌症治疗中的靶向核苷酸切除修复
- 批准号:
8652165 - 财政年份:2013
- 资助金额:
$ 49.69万 - 项目类别:
Development of Novel Agents Targeting Genome Stability and Maintenance for Treati
针对治疗的基因组稳定性和维持的新型药物的开发
- 批准号:
8649744 - 财政年份:2013
- 资助金额:
$ 49.69万 - 项目类别:
Targeting nucleotide excision repair in combination cancer therapy
联合癌症治疗中的靶向核苷酸切除修复
- 批准号:
8898026 - 财政年份:2013
- 资助金额:
$ 49.69万 - 项目类别:
Targeting nucleotide excision repair in combination cancer therapy
联合癌症治疗中的靶向核苷酸切除修复
- 批准号:
8743197 - 财政年份:2013
- 资助金额:
$ 49.69万 - 项目类别:
Development of Novel Agents Targeting Genome Stability and Maintenance for Treati
针对治疗的基因组稳定性和维持的新型药物的开发
- 批准号:
8201446 - 财政年份:2012
- 资助金额:
$ 49.69万 - 项目类别:
Development of methodologies for the analysis of DNA repair capacity to predict t
开发分析 DNA 修复能力以预测 t 的方法
- 批准号:
7434231 - 财政年份:2008
- 资助金额:
$ 49.69万 - 项目类别:
Development of methodologies for the analysis of DNA repair capacity to predict t
开发分析 DNA 修复能力以预测 t 的方法
- 批准号:
7682236 - 财政年份:2008
- 资助金额:
$ 49.69万 - 项目类别:
RECOGNITION AND REPAIR OF CISPLATIN DNA DAMAGE
顺铂 DNA 损伤的识别和修复
- 批准号:
6633491 - 财政年份:2000
- 资助金额:
$ 49.69万 - 项目类别:
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