"DNMT and TET1 reprogramming as a targetable mechanism of resistance in advanced prostate cancer"
“DNMT 和 TET1 重编程作为晚期前列腺癌的靶向耐药机制”
基本信息
- 批准号:10681632
- 负责人:
- 金额:$ 66.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:ASCL1 geneAddressAdenocarcinomaAndrogen AntagonistsAndrogen ReceptorAndrogensAntiandrogen TherapyAutomobile DrivingCRISPR/Cas technologyCancer PatientCastrationCell Differentiation processCell SurvivalChromatinClinicalDNA MethylationDNA Modification MethylasesDNA Sequence AlterationDNMT3B geneDataDevelopmentDiseaseEpigenetic ProcessEpitheliumFutureGene ExpressionGenetic ModelsGenetically Engineered MouseGenomeGoalsHistologicIn VitroInterventionKnock-outMYCN geneMaintenanceMalignant NeoplasmsMalignant neoplasm of prostateMediatorMethylationModelingMolecularNeoplasm MetastasisNeuroendocrine Prostate CancerNeurosecretory SystemsOrganOrganoidsPatient SelectionPatientsPhenotypeProcessPrognosisProstateProstate AdenocarcinomaProstate Cancer therapyProtein MethylationPublishingRB1 geneReaderReceptor InhibitionReceptor SignalingRegulationResistanceRoleSiteSmall Cell CarcinomaSpecificityTherapeuticTimeVisceralWithdrawalXenograft procedureadvanced prostate cancerandrogen sensitiveantagonistbiomarker drivencancer typecastration resistant prostate cancerclinically relevantdeprivationeffective therapyenzalutamideepigenomeepigenomicsin vivoinsightmultidisciplinarymutantneoplastic cellnovelpersonalized cancer carepharmacologicpreventprogramsprostate cancer cellprostate cancer progressionresistance mechanismsynergismtargeted agenttargeted treatmenttranscription factortranscriptometumor
项目摘要
Project Summary/Abstract
Prostate cancer arises as an androgen driven disease and therefore androgen receptor (AR) targeting therapies
have been a major focus of prostate cancer treatment. Lineage
lose
mechanism
cancer histologic transformation from an AR-positive prostate adenocarcinoma to
an AR-negative small cell carcinoma that expresses neuroendocrine markers, often referred to as
neuroendocrine prostate cancer (NEPC). NEPC is clinically aggressive and prognosis is poor. Therefore,
effective treatment for NEPC patients remains an unmet clinical need. A thorough molecular understanding of
NEPC progression is needed for the development of effective treatments for this lethal disease. Although NEPC
tumors arise clonally from prostate adenocarcinoma and share genomic alterations, there is significant
epigenetic deregulation during the transformation process. However, mechanistically, we still do not know how
these epigenetic alterations arise and how best to leverage these alterations as a therapeutic opportunity. Our
preliminary and published data from in vivo, in vitro and ex vivo models (NEPC-patient-derived organoids)
suggest that the N-Myc transcriptome and cistrome is androgen-dependent and drives epithelial plasticity and
the acquisition of clinically-relevant, NEPC molecular program and a reprogramming of the epigenome. Most
recently, based on data from a new genetically engineered mouse model (GEMs), we found that N-Myc induction
synergizes with RB1 loss to deregulate DNA methylation readers, writers (e.g. DNMT1 and DNMT3B) and
erasures (e.g. TET1). Interestingly, we and others have shown that specific molecular or pharmacological
interventions can revert NEPC phenotype to a luminal—more clinically manageable—adenocarcinoma
phenotype. Our over-arching hypothesis, which is based on our published and preliminary data, is that specific
molecular alterations (e.g. MYCN induction/RB1 loss) in prostate cancer cells drive lineage plasticity through
epigenetic reprogramming (i.e., DNA methylation) as a mechanism of resistance to anti-AR therapy and this
leads to transformation to NEPC. To address this hypothesis, we will employ patient-derived organoids and
xenograft and novel genetically engineered mouse models to elucidate the role and specificity of DNMTs/TET1
in establishing the NEPC-related DNA methylation program (Aim 1), characterize the upstream regulation of
DNMTs expression in the progression to NEPC (Aim 2) and to assess the therapeutic potential of DNMTs
inhibition alone or in combination with AR targeted therapy to block the transition to or maintenance of NEPC
(Aim 3). Successful completion of these Aims will provide unique insights into NEPC development, identify key
and potential targetable mediators of lineage plasticity, and provide rationale for future clinical strategies to target
the underlying epigenetic mechanisms that drive the transition from prostate adenocarcinoma to NEPC.
plasticity, a process by which differentiated cells
their identity and acquire alternative lineage programs, has recently been identified as an emerging
of resistance to targeted therapies in several cancer types including prostate cancer prostate
this plasticity can manifest as
. For
项目总结/摘要
前列腺癌是一种雄激素驱动的疾病,因此雄激素受体(AR)靶向治疗
一直是前列腺癌治疗的主要焦点。谱系
失去
机制
从AR阳性前列腺癌到
一种表达神经内分泌标志物的AR阴性小细胞癌,通常被称为
神经内分泌前列腺癌(NEPC)。NEPC临床上具有侵袭性,预后差。因此,我们建议,
NEPC患者的有效治疗仍然是未满足的临床需求。从分子水平全面了解
NEPC的进展是开发这种致命疾病的有效治疗所必需的。虽然NEPC
肿瘤从前列腺腺癌克隆产生并共享基因组改变,
转化过程中的表观遗传失调。然而,从机制上讲,我们仍然不知道如何
这些表观遗传改变的出现以及如何最好地利用这些改变作为治疗机会。我们
来自体内、体外和离体模型(NEPC患者源性类器官)的初步和已发表数据
表明N-Myc转录组和顺式组是雄激素依赖性的,并驱动上皮可塑性,
获得临床相关的NEPC分子程序和表观基因组的重编程。最
最近,基于一种新的基因工程小鼠模型(GEMs)的数据,我们发现N-Myc诱导
与RB 1丢失协同作用,解除DNA甲基化读取器、写入器(例如DNMT 1和DNMT 3B)和
擦除(例如TET 1)。有趣的是,我们和其他人已经表明,特定的分子或药理学
干预可以将NEPC表型逆转为临床上更易处理的管腔腺癌
表型我们的过度兴奋假设是基于我们公布的和初步的数据,
前列腺癌细胞中的分子改变(例如MYCN诱导/RB 1丢失)通过以下方式驱动谱系可塑性:
表观遗传重编程(即,DNA甲基化)作为抗AR疗法抗性的机制,并且这
导致向NEPC的转变。为了解决这一假设,我们将采用患者来源的类器官,
异种移植和新型基因工程小鼠模型,以阐明DNMTs/TET 1的作用和特异性
在建立NEPC相关的DNA甲基化程序(目标1)时,
DNMT在NEPC进展中的表达(目的2),并评估DNMT的治疗潜力
单独抑制或与AR靶向治疗联合,以阻断向NEPC的转变或维持NEPC
(Aim(3)第三章。成功完成这些目标将为NEPC的发展提供独特的见解,确定关键的
以及潜在的可靶向的谱系可塑性介质,并为未来的临床策略提供理论基础,
驱动前列腺腺癌向NEPC转变的潜在表观遗传机制。
可塑性,一个分化细胞
他们的身份和获得替代血统计划,最近被确定为一个新兴的
对靶向治疗的耐药性,包括前列腺癌
这种可塑性可以表现为
.为
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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Himisha Beltran其他文献
Himisha Beltran的其他文献
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{{ truncateString('Himisha Beltran', 18)}}的其他基金
Molecular Determinants of Response and Resistance to EZH2 and PARP inhibition in Prostate Cancer
前列腺癌中 EZH2 和 PARP 抑制反应和耐药性的分子决定因素
- 批准号:
10628273 - 财政年份:2023
- 资助金额:
$ 66.29万 - 项目类别:
Molecular mechanisms underlying lineage plasticity in prostate cancer
前列腺癌谱系可塑性的分子机制
- 批准号:
10375455 - 财政年份:2020
- 资助金额:
$ 66.29万 - 项目类别:
Molecular mechanisms underlying lineage plasticity in prostate cancer
前列腺癌谱系可塑性的分子机制
- 批准号:
10596605 - 财政年份:2020
- 资助金额:
$ 66.29万 - 项目类别:
Project 1: Non-Invasive Clinical Assay for Early Detection of Treatment Resistance in Patients with Metastatic Prostate Cancer
项目1:早期检测转移性前列腺癌患者治疗耐药性的非侵入性临床检测
- 批准号:
10227729 - 财政年份:2017
- 资助金额:
$ 66.29万 - 项目类别:
Project 1: Non-Invasive Clinical Assay for Early Detection of Treatment Resistance in Patients with Metastatic Prostate Cancer
项目1:早期检测转移性前列腺癌患者治疗耐药性的非侵入性临床检测
- 批准号:
9357038 - 财政年份:
- 资助金额:
$ 66.29万 - 项目类别:
Project 1: Non-Invasive Clinical Assay for Early Detection of Treatment Resistance in Patients with Metastatic Prostate Cancer
项目1:早期检测转移性前列腺癌患者治疗耐药性的非侵入性临床检测
- 批准号:
9763525 - 财政年份:
- 资助金额:
$ 66.29万 - 项目类别:
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