ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient Prostate Cancer.
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点。
基本信息
- 批准号:10034539
- 负责人:
- 金额:$ 13.03万
- 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:2020-06-08 至 2020-09-30
- 项目状态:已结题
- 来源:
- 关键词:ATR geneAdoptedAndrogen ReceptorAutomobile DrivingBasal CellCRISPR/Cas technologyCancer PatientCarboplatinCastrationCellsCharacteristicsClinicalClinical TrialsCombined Modality TherapyDNA DamageDNA RepairDNA Repair InhibitionDNA Repair PathwayDataDependenceDiseaseDouble Strand Break RepairEZH2 geneEarly identificationEnhancersEpigenetic ProcessFrequenciesGenesGeneticHomologous GeneHypersensitivityImmunotherapyInterceptKRP proteinKnowledgeMalignant neoplasm of prostateMediatingMetastatic Prostate CancerMitotic CheckpointModelingMolecularMulti-Institutional Clinical TrialMusNeurosecretory SystemsNonhomologous DNA End JoiningOutcomePathway interactionsPatientsPhenotypePhosphotransferasesPre-Clinical ModelPredispositionProstateProtein InhibitionProtein-Serine-Threonine KinasesQuality of lifeRB1 geneReceptor SignalingResearch PersonnelResistanceRetinoblastomaSamplingSignal TransductionTP53 geneTestingTherapeuticUpdateValidationWorkandrogen deprivation therapycheckpoint therapydocetaxelds-DNAfunctional genomicsgenome-wideimmune checkpoint blockadeimmunogenicityinhibitor/antagonistinnate immune pathwaysinnovationloss of functionmortalitymouse modelnew therapeutic targetnovelnovel therapeutic interventionpre-clinicalprostate cancer cellprostate cancer cell linereceptor expressionrepairedresistance mechanismresistance mutationresponsestem cellssynergismtherapeutic targettherapy resistanttreatment strategytumor
项目摘要
PROJECT SUMMARY
Metastatic prostate cancer (mPCa) is incurable and responsible for the majority of PC associated mortality.
Therefore, there is a critical need to identify drivers of mPCa to enable early identification and interceptive
therapeutic strategies to provide durable responses in patients. Androgen deprivation therapy (ADT) is the
primary line of treatment for mPCa. ADT initially extends survival but is not curative as the patient’s tumor
acquires castration resistance (mCRPC). A majority of mCRPC remain dependent on the function of the androgen
receptor (AR), though due to the inclusion of more potent AR antagonist (eg: enzalutamide) has led to the
emergence, in a subset of cases (approximately 20%), of resistance mechanisms independent of AR activity
(CRPC-AI). CRPC-AI adapt to ADT via lineage plasticity rather than a result of resistant mutations, adopting a
phenotype no longer reliant on AR expression and signaling. These tumors may display neuroendocrine features,
a stem or basal cell-like phenotype, altered kinase signaling, and characteristic epigenetic alterations. Recently,
we and others have characterized the molecular landscape of CRPC-AI and have identified and validated new
therapeutic targets and drivers, including loss of Retinoblastoma-1 (RB) and TP53, and induction of specific
epigenetic/reprogramming factors such as (Enhancer of Zeste Homolog 2) EZH2 and SOX2.
Additionally, our work validated the importance of EZH2 reprogramming downstream of RB1 loss, driving
lineage plasticity and resistance to ADT. Moreover, inhibition of EZH2 enabled lineage reversal and re-sensitized
RB loss prostate cancer to ADT. Importantly, recent data from patients with mCRPC identified RB genetic
aberrations as the strongest predictor of poor outcome. These data implicate RB as a dominant molecular
mechanism driving lethal prostate cancer. Currently there is no therapeutic option to provide durable
response in patients with RB loss-of-function (LOF). Therefore, there is a critical need to delineate
downstream effectors of RB LOF so that therapeutic targets can be identified and validated in clinical
trials. Specific to this application, our functional genomic screen has identified dependence on DNA damage
repair kinases – specifically – ATR. This proposed work is innovative because it will provide deeper mechanistic
knowledge of drivers of RB deficient prostate cancer and therapeutic options towards a currently untreatable
phenotype. Through this work we will validate the ability of DDR kinase targeting to exacerbate DDR deficiency
and to generate hypersensitivity in RB-deficient prostate models (Aim 1), determine the correlation between RB
function, HR proficiency and response to M6620+carboplatin and docetaxel+carboplatin in preclinical models
and clinical samples (Aim 2), and evaluate synergy of ATR kinase inhibition, EZH2 inhibition, and immune
checkpoint blockade therapy in pre-clinical RB-deficient prostate mouse models (Aim 3). Ultimately, this
information will enable us to gather sufficient preliminary evidence to make a compelling case to commence
investigator-initiated multi-center clinical trials.
项目总结
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Leigh Ellis其他文献
Leigh Ellis的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Leigh Ellis', 18)}}的其他基金
Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer
鉴定 RB 缺陷型前列腺癌中 EZH2 依赖性脆弱性
- 批准号:
10410374 - 财政年份:2021
- 资助金额:
$ 13.03万 - 项目类别:
Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer
鉴定 RB 缺陷型前列腺癌中 EZH2 依赖性脆弱性
- 批准号:
10154294 - 财政年份:2021
- 资助金额:
$ 13.03万 - 项目类别:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点
- 批准号:
10304098 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点
- 批准号:
10186723 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点
- 批准号:
10472549 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer
利用 RB1 缺陷治疗致命性神经内分泌前列腺癌
- 批准号:
9763338 - 财政年份:2016
- 资助金额:
$ 13.03万 - 项目类别:
Novel Mouse Models to define Genetic Drivers of Aggressive Prostate Cancer
定义侵袭性前列腺癌遗传驱动因素的新型小鼠模型
- 批准号:
9461668 - 财政年份:2016
- 资助金额:
$ 13.03万 - 项目类别:
Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer
利用 RB1 缺陷治疗致命性神经内分泌前列腺癌
- 批准号:
9338195 - 财政年份:2016
- 资助金额:
$ 13.03万 - 项目类别:
Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer
利用 RB1 缺陷治疗致命性神经内分泌前列腺癌
- 批准号:
9152986 - 财政年份:2016
- 资助金额:
$ 13.03万 - 项目类别:
相似海外基金
How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
- 批准号:
2315783 - 财政年份:2023
- 资助金额:
$ 13.03万 - 项目类别:
Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
- 批准号:
2719534 - 财政年份:2022
- 资助金额:
$ 13.03万 - 项目类别:
Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
- 批准号:
20K01113 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633211 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2436895 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633207 - 财政年份:2020
- 资助金额:
$ 13.03万 - 项目类别:
Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
- 批准号:
19K01745 - 财政年份:2019
- 资助金额:
$ 13.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
- 批准号:
426559561 - 财政年份:2019
- 资助金额:
$ 13.03万 - 项目类别:
Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
- 批准号:
2236701 - 财政年份:2019
- 资助金额:
$ 13.03万 - 项目类别:
Studentship
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
- 批准号:
415543446 - 财政年份:2019
- 资助金额:
$ 13.03万 - 项目类别:
Research Fellowships