Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
基本信息
- 批准号:10533264
- 负责人:
- 金额:$ 40.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-05 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Antiestrogen TherapyBiopsyBloodBreast Cancer PatientBreast Cancer TreatmentCell LineClinicalDataDiseaseDisease ProgressionDrug resistanceERBB2 geneESR1 geneEngineeringEpidermal Growth Factor ReceptorEstrogen ReceptorsEstrogen receptor positiveEvolutionFRAP1 geneFulvestrantFundingFutureGenesGenetic TranscriptionGenomicsGoalsHormonalLigand Binding DomainMAP Kinase GeneMEKsMapsMediatingMetastatic breast cancerMethodologyMitogen-Activated Protein KinasesModelingMolecularMolecular ProfilingMonitorMutationNF1 geneNF1 mutationPI3K/AKTPathway interactionsPatientsPopulationPre-Clinical ModelReceptor GeneRecording of previous eventsRecurrenceResistanceSamplingSelection for TreatmentsSignal TransductionSpecimenTherapeuticTherapeutic AgentsTimeWorkcell free DNAco-clinical trialcohortcombinatorialdrug sensitivityhormone therapyinhibitorinsightkinase inhibitormalignant breast neoplasmmutantnext generation sequencingnovel therapeutic interventionpatient derived xenograft modelpatient responsepressurepreventprospectiveresistance mechanismresponsetargeted sequencingtherapy resistanttreatment responsetumortumor progression
项目摘要
ABSTRACT
Hormonal therapy remains a mainstay of systemic treatment for the 70% of breast cancers that express the
estrogen receptor (ER), but responses vary and intrinsic and acquired resistance are major clinical challenges.
Recently, ligand-binding domain mutations in the estrogen receptor (ER) gene (ESR1) were found to occur and
to mediate hormonal therapy resistance in approximately 35% of ER-positive (ER+) breast cancer patients. In
the remaining two-thirds of cases, the molecular basis of hormonal therapy resistance is largely unknown. In
preliminary data, based on targeted sequencing of 1756 breast cancer patients with recurrent or metastatic
disease, we identified enrichment for alterations in diverse effectors of MAP kinase signaling (ERBB2 mutation,
EGFR amplification, NF1 mutation, and others) in ESR1-wildtype breast cancers collected after disease
progression on anti-estrogen therapy. This proposal is based on the hypothesis that recent advances in
sequencing methodology and analysis of cell-free DNA (cfDNA) can prospectively identify molecular alterations
that confer resistance to hormonal therapy in patients with breast cancer and that co-targeting such alterations
alongside ER could prevent or delay the emergence of drug-resistant clones. Three specific aims are
proposed. In Aim 1, paired tumor samples and cfDNA collected from breast cancer patients before and during
treatment and at the time of disease progression on hormonal therapy will be used to define the landscape and
timing of molecular changes that arise under the selective pressure of therapy. Our preliminary data indicate
that ERBB2 mutation is a mechanism of both intrinsic and acquired resistance to hormonal therapy. We have
also found that the HER kinase inhibitor neratinib can induce profound therapeutic responses that are limited
by the induction of ER activity and consequent emergence of drug resistance. Thus, in Aim 2, we will use
paired pretreatment and disease-progression tumor biopsies, cfDNA collected at regular intervals during
treatment with neratinib alone or with the ER degrader fulvestrant, and engineered isogenic models and
patient-derived xenografts to identify and validate mechanisms of resistance to these therapeutic agents.
Finally, our genomic analysis identified RAS/ERK pathway alterations in ~10% of tumors collected following
disease progression on hormonal therapy. In Aim 3, we will explore the functional significance of this finding
and seek to develop therapeutic strategies for overcoming hormonal therapy resistance in this molecularly
defined population. The long-term objective of this project is to develop therapeutic strategies for ER+ breast
cancer guided by real-time, non-invasive molecular monitoring of tumor evolution. The work proposed will also
generate valuable preclinical models of HER2-mutant and NF1-mutant ER+ breast cancer that can be used in
future studies to assess promising novel therapeutic approaches for these molecularly defined populations.
抽象的
激素疗法仍然是70%表达乳腺癌的全身治疗的主要手段
雌激素受体(ER),但反应变化,内在和获得的耐药性是主要的临床挑战。
最近,发现雌激素受体(ER)基因(ESR1)中的配体结合结构域突变发生,并且发生
在大约35%的ER阳性(ER+)乳腺癌患者中介导荷尔蒙治疗抗性。在
其余三分之二的病例,激素疗法抗性的分子基础在很大程度上尚不清楚。在
初步数据,基于1756例复发或转移性乳腺癌患者的靶向测序
疾病,我们确定了MAP激酶信号传导不同效应因子的改变(ERBB2突变,,
EGFR扩增,NF1突变等)在疾病后收集的ESR1 WildType乳腺癌中
抗雌激素治疗的进展。该提议基于以下假设。
测序方法论和无细胞DNA(CFDNA)的分析可以前瞻性地识别分子改变
在乳腺癌患者中赋予对激素疗法的抗药性,并促进此类改变
与ER一起可以防止或延迟耐药克隆的出现。三个具体目标是
建议的。在AIM 1中,从乳腺癌患者中收集的配对肿瘤样品和CFDNA之前和期间
治疗和在疾病进展时,将使用荷尔蒙治疗的治疗来定义景观和
在治疗选择性压力下出现的分子变化的时机。我们的初步数据表示
这种ERBB2突变是对激素治疗的内在耐药性和获得性的一种机制。我们有
还发现她的激酶抑制剂neratinib可以诱导有限的深刻治疗反应
通过诱导ER活性和随之而来的耐药性出现。因此,在AIM 2中,我们将使用
配对预处理和疾病产生肿瘤活检,在cfDNA中定期收集
单独或单独或用ER降解器征服者治疗,设计的等源性模型和
患者衍生的异种移植物以识别和验证对这些治疗剂的抗性机制。
最后,我们的基因组分析确定了〜10%收集的肿瘤的RAS/ERK途径改变
激素治疗的疾病进展。在AIM 3中,我们将探讨该发现的功能意义
并寻求制定治疗策略,以克服该分子中的荷尔蒙治疗耐药性
定义的人口。该项目的长期目标是为ER+乳房制定治疗策略
癌症是由肿瘤进化的实时,非侵入性分子监测的指导。提议的工作也将
生成可用于用于用于用于的HER2突变剂和NF1突变乳腺癌的宝贵临床前模型
未来的研究,以评估这些分子定义的人群的有希望的新型治疗方法。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer.
- DOI:10.1158/1078-0432.ccr-23-0011
- 发表时间:2023-08-01
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS.
- DOI:10.1038/s41467-021-24109-5
- 发表时间:2021-06-18
- 期刊:
- 影响因子:16.6
- 作者:Rose Brannon A;Jayakumaran G;Diosdado M;Patel J;Razumova A;Hu Y;Meng F;Haque M;Sadowska J;Murphy BJ;Baldi T;Johnson I;Ptashkin R;Hasan M;Srinivasan P;Rema AB;Rijo I;Agarunov A;Won H;Perera D;Brown DN;Samoila A;Jing X;Gedvilaite E;Yang JL;Stephens DP;Dix JM;DeGroat N;Nafa K;Syed A;Li A;Lebow ES;Bowman AS;Ferguson DC;Liu Y;Mata DA;Sharma R;Yang SR;Bale T;Benhamida JK;Chang JC;Dogan S;Hameed MR;Hechtman JF;Moung C;Ross DS;Vakiani E;Vanderbilt CM;Yao J;Razavi P;Smyth LM;Chandarlapaty S;Iyer G;Abida W;Harding JJ;Krantz B;O'Reilly E;Yu HA;Li BT;Rudin CM;Diaz L;Solit DB;Arcila ME;Ladanyi M;Loomis B;Tsui D;Berger MF;Zehir A;Benayed R
- 通讯作者:Benayed R
Utility of Serial cfDNA NGS for Prospective Genomic Analysis of Patients on a Phase I Basket Study.
使用连续 cfDNA NGS 对 I 期篮子研究中的患者进行前瞻性基因组分析。
- DOI:10.1200/po.20.00184
- 发表时间:2021
- 期刊:
- 影响因子:4.6
- 作者:Smyth,LillianM;Reichel,JonathanB;Tang,Jiabin;Patel,JuberAhamadA;Meng,Fanli;Selcuklu,DuyguS;Houck-Loomis,Brian;You,Daoqi;Samoila,Aliaksandra;Schiavon,Gaia;Li,BobT;Razavi,Pedram;Piscuoglio,Salvatore;Reis-Filho,JorgeS;Taylo
- 通讯作者:Taylo
Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.
对 4854 名患者的系统分析揭示了 ESR1 野生型转移性乳腺癌中激酶融合的富集。
- DOI:10.1016/j.annonc.2020.04.008
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Ross,DS;Liu,B;Schram,AM;Razavi,P;Lagana,SM;Zhang,Y;Scaltriti,M;Bromberg,JF;Ladanyi,M;Hyman,DM;Drilon,A;Zehir,A;Benayed,R;Chandarlapaty,S;Hechtman,JF
- 通讯作者:Hechtman,JF
Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients.
- DOI:10.1186/s13073-021-00898-8
- 发表时间:2021-05-31
- 期刊:
- 影响因子:12.3
- 作者:Tsui DWY;Cheng ML;Shady M;Yang JL;Stephens D;Won H;Srinivasan P;Huberman K;Meng F;Jing X;Patel J;Hasan M;Johnson I;Gedvilaite E;Houck-Loomis B;Socci ND;Selcuklu SD;Seshan VE;Zhang H;Chakravarty D;Zehir A;Benayed R;Arcila M;Ladanyi M;Funt SA;Feldman DR;Li BT;Razavi P;Rosenberg J;Bajorin D;Iyer G;Abida W;Scher HI;Rathkopf D;Viale A;Berger MF;Solit DB
- 通讯作者:Solit DB
{{
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 }}
Sarat Chandarlapaty其他文献
Sarat Chandarlapaty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('Sarat Chandarlapaty', 18)}}的其他基金
HER2-mediated delivery of cytotoxic agents in solid tumors
实体瘤中 HER2 介导的细胞毒药物递送
- 批准号:
10381517 - 财政年份:2021
- 资助金额:
$ 40.26万 - 项目类别:
HER2-mediated delivery of cytotoxic agents in solid tumors
实体瘤中 HER2 介导的细胞毒药物递送
- 批准号:
10608129 - 财政年份:2021
- 资助金额:
$ 40.26万 - 项目类别:
Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
转移性乳腺癌 APOBEC 突变的诊断和治疗
- 批准号:
10237883 - 财政年份:2020
- 资助金额:
$ 40.26万 - 项目类别:
Defining the impact of mutant oncogene zygosity
定义突变癌基因接合性的影响
- 批准号:
10582527 - 财政年份:2020
- 资助金额:
$ 40.26万 - 项目类别:
Defining the impact of mutant oncogene zygosity
定义突变癌基因接合性的影响
- 批准号:
10362576 - 财政年份:2020
- 资助金额:
$ 40.26万 - 项目类别:
Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
转移性乳腺癌 APOBEC 突变的诊断和治疗
- 批准号:
10478015 - 财政年份:2020
- 资助金额:
$ 40.26万 - 项目类别:
Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
转移性乳腺癌 APOBEC 突变的诊断和治疗
- 批准号:
10704108 - 财政年份:2020
- 资助金额:
$ 40.26万 - 项目类别:
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10304866 - 财政年份:2018
- 资助金额:
$ 40.26万 - 项目类别:
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10054178 - 财政年份:2018
- 资助金额:
$ 40.26万 - 项目类别:
Therapeutic approaches to ER mutant breast cancer
ER突变乳腺癌的治疗方法
- 批准号:
9238168 - 财政年份:2017
- 资助金额:
$ 40.26万 - 项目类别:
相似国自然基金
肿瘤外泌体核酸甲基化标志物的鉴定及其在液体活检中的应用
- 批准号:22307101
- 批准年份:2023
- 资助金额:10 万元
- 项目类别:青年科学基金项目
基于微球透镜阵列的一体化检测芯片及其在肿瘤“液体活检”中应用的关键技术研究
- 批准号:62375121
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
近红外二区比率荧光双探针对转移前哨淋巴结的时间分辨活检
- 批准号:82302254
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于血浆cfDNA片段组学特征的液体活检技术在常见消化道肿瘤筛查中的应用研究
- 批准号:82373664
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
基于SERS光谱液体活检技术的鼻咽癌筛查研究
- 批准号:12374405
- 批准年份:2023
- 资助金额:53.00 万元
- 项目类别:面上项目
相似海外基金
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10304866 - 财政年份:2018
- 资助金额:
$ 40.26万 - 项目类别:
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10054178 - 财政年份:2018
- 资助金额:
$ 40.26万 - 项目类别:
A precision medicine basis for estrogen therapy for advanced breast cancer
晚期乳腺癌雌激素治疗的精准医学基础
- 批准号:
9888357 - 财政年份:2017
- 资助金额:
$ 40.26万 - 项目类别:
Combination Chemoprevention: Prevention of Both ER-Positive & ER-Negative BC
联合化学预防:预防 ER 阳性
- 批准号:
7385530 - 财政年份:2007
- 资助金额:
$ 40.26万 - 项目类别:
Combination Chemoprevention: Prevention of Both ER-Positive & ER-Negative BC
联合化学预防:预防 ER 阳性
- 批准号:
8182291 - 财政年份:
- 资助金额:
$ 40.26万 - 项目类别: