Epigenetic mechanisms of therapeutic resistance
Epigenetic mechanisms of therapeutic resistance
批准号:
10434103
负责人:
KORNELIA POLYAK
金额:
$35.88万
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
项目状态:
未结题
起止时间:
2020-09-11 至 2025-05-31
关键词:
ATAC-seqAffectBar CodesBreast Cancer CellBreast Cancer PatientBreast Cancer cell lineBromodomainCRISPR screenCRISPR/Cas technologyCell CountCellsChIP-seqChemoresistanceCombined Modality TherapyDataDevelopmentDisease ProgressionDisease-Free SurvivalDrug ToleranceEndocrineEnzymesEpigenetic ProcessEstrogen AntagonistsEstrogen receptor positiveEvolutionFrequenciesGeneticGenomicsGoalsHeterogeneityHistone H3HistonesHumanIn VitroIndividualKDM5B geneKnowledgeLysineMCF7 cellMammary NeoplasmsMolecularOncogenesPaclitaxelPharmaceutical PreparationsPharmacologyPhenotypePlayPopulationPopulation DecreasesPopulation DynamicsPrognosisPublishingRegulationReportingResearchResistanceRoleRouteSignal TransductionSpecificityTestingTherapeuticTherapeutic AgentsTimeValidationVariantacquired treatment resistanceanti-cancer therapeuticbasecancer cellcancer therapychemotherapydesigneffective therapyepigenetic drugepigenetic therapyepigenomicsexperimental studygenome-widehormone therapyimprovedin vivoinhibitormalignant breast neoplasmmathematical modelneoplasticnovel therapeuticsoverexpressionresistance mechanismresponsesingle-cell RNA sequencingsmall moleculetherapeutic targettherapy resistanttranscriptometranscriptomicstreatment responsetreatment strategytriple-negative invasive breast carcinomatumor
中文摘要
项目摘要/摘要
细胞表型异质性是肿瘤疾病进展和发展的关键机制
治疗耐药,但其调控在分子水平上知之甚少。我们发现这一数字上升了
治疗耐药性与更高水平的细胞间转录异质性相关,并且
通过调节表观遗传组蛋白修饰酶的活性来降低这种异质性
KDM5B可改善对治疗的反应。我们还确定了对表观遗传药物的获得性耐药性
药物,包括KDM5和BET溴域抑制剂,是由于表观遗传机制,而获得性
内分泌抵抗反映了对预先存在的、遗传上不同的亚群细胞的选择。目标是
本项目的目的是研究细胞表型异质性的种群动态
腔内雌激素受体阳性(ER+)和三阴性乳腺癌对肿瘤治疗的抵抗
(TNBC)。我们的假设是,由表观遗传调节器控制的细胞状态是高度可变和动态的
这是后天治疗抵抗的基础。我们还假设,通过调节神经元的活动,
通过鉴定合成致死性和获得性抗性的机制
表观遗传剂,我们可以减少转录异质性,提高治疗反应。测试我们的
假设,我们将表征遗传和表观遗传异质性对获得性抗性的影响。
内分泌、化疗和表观遗传疗法(目标1)。我们将使用条形码单元来跟踪种群动态
在获得性抗性的发展过程中,表征表观遗传格局和转录本
耐药和耐药群体的异质性,并在实验的基础上建立数学模型
用于预测不同药物治疗耐药性演变的数据。此外,为了定义合成致命
表观遗传疗法获得性耐药的相互作用和机制我们将进行CRISPR/Cas9
在ER+和TNBC细胞系中筛选对表观遗传剂敏感和耐药的细胞株(目标2)。总体而言,
该项目将极大地促进我们对表型异质性的调节以及这一作用的了解
在治疗反应和抵抗中发挥作用。
英文摘要
Project Summary/Abstract
Cellular phenotypic heterogeneity is a key mechanism underlying neoplastic disease progression and
therapeutic resistance, yet its regulation is poorly understood at the molecular level. We have found that elevated
therapeutic resistance is associated with higher levels of cell-to-cell transcriptomic heterogeneity and that
decreasing such heterogeneity by modulating the activity of epigenetic histone-modifying enzymes such as
KDM5B improves responses to treatment. We also determined that acquired resistance to epigenetic drug
agents, including KDM5 and BET bromodomain inhibitors, is due to epigenetic mechanisms, whereas acquired
endocrine resistance reflects a selection for a pre-existing, genetically distinct sub-populations of cells. The goal
of this Project is to investigate the population dynamics of cellular phenotypic heterogeneity in response to and
resistance to cancer therapies in luminal estrogen receptor positive (ER+) and triple-negative breast cancer
(TNBC). Our hypothesis is that cellular states governed by epigenetic regulators are highly variable and dynamic
and that this underlies acquired therapeutic resistance. We also hypothesize that by modulating the activity of
epigenetic regulators and by identifying mechanisms of synthetic lethality and the acquired resistance to
epigenetic agents, we can decrease transcriptomic heterogeneity and improve therapeutic response. To test our
hypotheses, we will characterize the impact of genetic and epigenetic heterogeneity on acquired resistance to
endocrine, chemo-, and epigenetic therapies (Aim 1). We will use barcoded cells to follow population dynamics
during the development of acquired resistance, characterize the epigenetic landscape and transcriptomic
heterogeneity of drug-tolerant and -resistant populations, and build mathematical models based on experimental
data to predict the evolution of therapeutic resistance to different agents. Additionally, to define synthetic-lethal
interactions and mechanism of acquired resistance to epigenetic therapies we will perform CRISPR/Cas9
screens (Aim 2) in ER+ and TNBC cell lines that are sensitive versus resistant to epigenetic agents. Overall, the
project will significantly advance our knowledge of the regulation of phenotypic heterogeneity and the role this
plays in therapeutic responses and resistance.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Administrative Core - New therapeutic vulnerabilities in breast cancer
-
批准号:10261469
-
项目类别:
-
资助金额:$11.58万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Epigenetic mechanisms of therapeutic resistance
-
批准号:10627962
-
项目类别:
-
资助金额:$35.88万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Administrative Core - New therapeutic vulnerabilities in breast cancer
-
批准号:10627981
-
项目类别:
-
资助金额:$11.34万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
New therapeutic vulnerabilities in breast cancer
-
批准号:10434102
-
项目类别:
-
资助金额:$171.86万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Epigenetic mechanisms of therapeutic resistance
-
批准号:10023397
-
项目类别:
-
资助金额:$36.61万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Administrative Core - New therapeutic vulnerabilities in breast cancer
-
批准号:10023400
-
项目类别:
-
资助金额:$12.49万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
New therapeutic vulnerabilities in breast cancer
-
批准号:10627961
-
项目类别:
-
资助金额:$171.86万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
New therapeutic vulnerabilities in breast cancer
-
批准号:10261465
-
项目类别:
-
资助金额:$175.37万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Epigenetic mechanisms of therapeutic resistance
-
批准号:10261466
-
项目类别:
-
资助金额:$36.61万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
New therapeutic vulnerabilities in breast cancer
-
批准号:10023396
-
项目类别:
-
资助金额:$177.3万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Administrative Core - New therapeutic vulnerabilities in breast cancer
-
批准号:10434106
-
项目类别:
-
资助金额:$11.34万
-
财政年份:2020
-
负责人:KORNELIA POLYAK
-
依托单位:
Targeting intratumor heterogeneity in breast cancer
-
批准号:10208794
-
项目类别:
-
资助金额:$115.71万
-
财政年份:2015
-
负责人:KORNELIA POLYAK
-
依托单位:
Targeting intratumor heterogeneity in breast cancer
-
批准号:9328033
-
项目类别:
-
资助金额:$54.67万
-
财政年份:2015
-
负责人:KORNELIA POLYAK
-
依托单位:
Project 3: Single Cell Measures of Intratumor Diversity for Optimal Breast Cancer Therapy
-
批准号:8866714
-
项目类别:
-
资助金额:$39.26万
-
财政年份:2015
-
负责人:KORNELIA POLYAK
-
依托单位:
Targeting intratumor heterogeneity in breast cancer
-
批准号:10705709
-
项目类别:
-
资助金额:$101.55万
-
财政年份:2015
-
负责人:KORNELIA POLYAK
-
依托单位:
The Role of P27 in Breast Epithelial Progenitors and Breast Cancer Risk
-
批准号:8633710
-
项目类别:
-
资助金额:$20.13万
-
财政年份:2014
-
负责人:KORNELIA POLYAK
-
依托单位:
Project 4: Combined use of immunotherapy and targeted treatments for triple negative breast cancer
-
批准号:10668347
-
项目类别:
-
资助金额:$30.18万
-
财政年份:2013
-
负责人:KORNELIA POLYAK
-
依托单位:
Core A: Administrative
-
批准号:10668335
-
项目类别:
-
资助金额:$20.15万
-
财政年份:2013
-
负责人:KORNELIA POLYAK
-
依托单位:
Project 4: Combined use of immunotherapy and targeted treatments for triple negative breast cancer
-
批准号:10215416
-
项目类别:
-
资助金额:$33.05万
-
财政年份:2013
-
负责人:KORNELIA POLYAK
-
依托单位:
Project 4: Combined use of immunotherapy and targeted treatments for triple negative breast cancer
-
批准号:10455693
-
项目类别:
-
资助金额:$29.06万
-
财政年份:2013
-
负责人:KORNELIA POLYAK
-
依托单位:
海外基金