Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition
通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性
基本信息
- 批准号:10631945
- 负责人:
- 金额:$ 39.1万
- 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:2020-09-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAcetylationAndrogen ReceptorBromodomainBromodomains and extra-terminal domain inhibitorCancer PatientCastrationCell SurvivalChIP-seqChromatinClinical TrialsDependenceDisease ProgressionDrug resistanceE2F transcription factorsExclusionGene ExpressionGenesGenetic TranscriptionGoalsHistologyHistone AcetylationHistone H3ImplantIn VitroLeadLysineMalignant neoplasm of prostateMeasuresModelingMusNeuroendocrine Prostate CancerNucleic Acid Regulatory SequencesOrganoidsPatientsPhenotypeProgram SustainabilityProstate AdenocarcinomaProteinsReaderReceptor SignalingRepressionReproducibilitySamplingSignal PathwaySystems BiologyTestingTimeTranscriptional ActivationVirulentXenograft procedureabirateronebiomarker identificationdesigneffective therapyenzalutamidehigh riskhistone acetyltransferaseloss of functionmenoutcome predictionpharmacologicphase I trialpredictive markerpreventprogramsprostate cancer cellprostate cancer cell linereceptor functionresistance mechanismresponseresponse biomarkertranscription factortranscriptome sequencingtreatment risktreatment strategytumortumor growth
项目摘要
Lineage plasticity in prostate cancer cells—defined as loss of androgen receptor (AR) signaling and switch
from a luminal to an alternate differentiation program—is now recognized as a critical determinant of lethality in
prostate cancer. The most virulent form is neuroendocrine prostate cancer (NEPC). De novo NEPC is rare
(<1% of patients). However, we recently found that castration-induced, treatment-emergent (t-NEPC) is much
more frequently found in tumors from men resistant to drugs such as abiraterone or enzalutamide. This
strongly suggests AR interference promotes the emergence of this phenotype. There are no effective therapies
for t-NEPC, and t-NEPC patients are often excluded from clinical trials due to t-NEPC’s aggressiveness. Thus,
there is a clear need to develop new treatments.
Recently, we discovered that specific transcription factors (TFs) and the BET bromodomain protein BRD4
cooperate to promote t-NEPC differentiation and cell survival. This application is designed to clarify
mechanisms by which these TF and BRD4 function and to block those mechanisms. Our long term goal is to
develop pharmacological strategies that prevent the emergence of lethal t-NEPC. Towards that goal, we
determined that targeting BET bromodomain proteins with BET inhibitors (BETi) or BET PROTAC degraders
(BETd) is a promising approach to block the lineage switch to t-NEPC and to block t-NEPC cell survival in vitro.
The studies we describe herein are designed to test the hypotheses that BRD4 and cooperating TFs activate
a lineage plasticity program that sustains survival of t-NEPC cells; targeting this BRD4/TF axis is a rational
approach to prevent or delay t-NEPC disease progression.
Aim 1: Determine mechanisms by which BRD4 cooperates with specific TFs to promote expression of
a t-NEPC lineage plasticity survival program. Completion of this aim will provide a detailed understanding of
how BRD4 and cooperating factors promote lineage plasticity and will determine whether activation of these
TFs is reliable predictive marker of favorable BET inhibitor response.
Aim 2: Treat t-NEPC patient tumors implanted in mice with BETi or BETd and measure anti-tumor
activity and NEPC differentiation. Completion of this aim will provide the rationale for BETi or BETd clinical
trials in t-NEPC patients and identify adaptive resistance mechanisms.
Aim 3: Prevent castration-induced t-NEPC lineage switch with BETi or BETd using a patient tumor
model of t-NEPC lineage switch implanted in mice. Completion of this aim will provide the rationale to test
BETi or BETd in patients at high-risk for t-NEPC conversion and identify biomarkers of response.
We expect that the studies proposed will clarify mechanistically the function of transcriptional network that
is critical for the emergence and survival of t-NEPC. These results will help identify new approches to block this
network in men with t-NEPC in the near-term.
前列腺癌细胞的谱系可塑性-定义为雄激素受体(AR)信号转导和开关的丢失
从管腔到交替分化程序-现在被认为是致命性的关键决定因素,
前列腺癌最致命的形式是神经内分泌前列腺癌(NEPC)。新发NEPC很少见
(<1%的患者)。然而,我们最近发现阉割诱导的治疗后出现的(t-NEPC)要多得多
更常见于对阿比特龙或恩杂鲁胺等药物耐药的男性肿瘤。这
强烈表明AR干扰促进了这种表型的出现。没有有效的治疗方法
由于t-NEPC的侵袭性,t-NEPC患者经常被排除在临床试验之外。因此,在本发明中,
显然需要开发新的治疗方法。
最近,我们发现特异性转录因子(TF)和BET布罗莫结构域蛋白BRD 4
协同促进t-NEPC分化和细胞存活。本申请旨在澄清
这些TF和BRD 4发挥作用的机制,并阻断这些机制。我们的长期目标是
开发预防致命t-NEPC出现的药理学策略。为了实现这一目标,我们
确定用BET抑制剂(BETi)或BET PROTAC降解剂靶向BET溴结构域蛋白
(BETd)是一种很有前途的方法,可以阻止谱系向t-NEPC的转变并阻止t-NEPC细胞在体外存活。
我们在此描述的研究旨在检验BRD 4和协作TF激活
维持t-NEPC细胞存活的谱系可塑性程序;靶向BRD 4/TF轴是合理的
预防或延迟t-NEPC疾病进展的方法。
目的1:确定BRD 4与特定TF合作以促进BRD 4表达的机制。
一个t-NEPC谱系可塑性存活程序。完成这一目标将提供一个详细的了解,
BRD 4和协同因子如何促进谱系可塑性,并将决定这些因子的激活是否
TF是有利的BET抑制剂反应的可靠预测标志物。
目的2:用BETi或BETd治疗植入小鼠中的t-NEPC患者肿瘤并测量抗肿瘤
活性和NEPC分化。这一目标的完成将为BETi或BETd临床提供依据
在t-NEPC患者中进行试验,并确定适应性耐药机制。
目的3:使用患者肿瘤,用BETi或BETd预防去势诱导的t-NEPC谱系转换
小鼠中植入的t-NEPC谱系转换模型。这一目标的完成将为测试提供依据
在t-NEPC转换的高风险患者中测定BETi或BETd,并确定反应的生物标志物。
我们希望这些研究能够从机制上阐明转录网络的功能,
对于t-NEPC的出现和存活至关重要。这些结果将有助于确定新的方法来阻止这一点
在短期内与t-NEPC的男性网络。
项目成果
期刊论文数量(0)
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Joshi James Alumkal其他文献
Joshi James Alumkal的其他文献
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{{ truncateString('Joshi James Alumkal', 18)}}的其他基金
Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition
通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性
- 批准号:
10220910 - 财政年份:2020
- 资助金额:
$ 39.1万 - 项目类别:
Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition
通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性
- 批准号:
10026750 - 财政年份:2020
- 资助金额:
$ 39.1万 - 项目类别:
Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition
通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性
- 批准号:
10405627 - 财政年份:2020
- 资助金额:
$ 39.1万 - 项目类别:
The Role of LSD1 in the Evolution of Castration Resistant Prostate Cancer
LSD1 在去势抵抗性前列腺癌演变中的作用
- 批准号:
8759224 - 财政年份:2014
- 资助金额:
$ 39.1万 - 项目类别:
The Role of LSD1 in the Evolution of Castration Resistant Prostate Cancer
LSD1 在去势抵抗性前列腺癌演变中的作用
- 批准号:
8879069 - 财政年份:2014
- 资助金额:
$ 39.1万 - 项目类别:
Targeting LSD1 in Neuroendocrine Prostate Cancer
靶向 LSD1 治疗神经内分泌前列腺癌
- 批准号:
10266055 - 财政年份:2014
- 资助金额:
$ 39.1万 - 项目类别:
The Role of LSD1 in the Evolution of Castration Resistant Prostate Cancer
LSD1 在去势抵抗性前列腺癌演变中的作用
- 批准号:
9090037 - 财政年份:2014
- 资助金额:
$ 39.1万 - 项目类别:
Targeting LSD1 in Neuroendocrine Prostate Cancer
靶向 LSD1 治疗神经内分泌前列腺癌
- 批准号:
10045656 - 财政年份:2014
- 资助金额:
$ 39.1万 - 项目类别:
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