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: 10533264
• 负责人: Sarat Chandarlapaty
• 金额: $ 40.26万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10533264
• 关键词: Antiestrogen Therapy; Biopsy; Blood; Breast Cancer Patient; Breast Cancer Treatment; Cell Line; Clinical; Data; Disease; Disease Progression; Drug resistance; ERBB2 gene; ESR1 gene; Engineering; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogen receptor positive; Evolution; FRAP1 gene; Fulvestrant; Funding; Future; Genes; Genetic Transcription; Genomics; Goals; Hormonal; Ligand Binding Domain; MAP Kinase Gene; MEKs; Maps; Mediating; Metastatic breast cancer; Methodology; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Monitor; Mutation; NF1 gene; NF1 mutation; PI3K/AKT; Pathway interactions; Patients; Population; Pre-Clinical Model; Receptor Gene; Recording of previous events; Recurrence; Resistance; Sampling; Selection for Treatments; Signal Transduction; Specimen; Therapeutic; Therapeutic Agents; Time; Work; cell free DNA; co-clinical trial; cohort; combinatorial; drug sensitivity; hormone therapy; inhibitor; insight; kinase inhibitor; malignant breast neoplasm; mutant; next generation sequencing; novel therapeutic intervention; patient derived xenograft model; patient response; pressure; prevent; prospective; resistance mechanism; response; targeted sequencing; therapy resistant; treatment response; tumor; tumor progression

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.

摘要 激素治疗仍然是70%的乳腺癌系统治疗的主要手段， 雌激素受体（ER），但反应各不相同，内在和获得性耐药性是主要的临床挑战。 最近，雌激素受体（ER）基因（ESR 1）中的配体结合结构域突变被发现发生， 在大约35%的ER阳性（ER+）乳腺癌患者中介导激素治疗抵抗。在 在其余三分之二的病例中，激素治疗抵抗的分子基础基本上是未知的。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，我们鉴定了MAP激酶信号传导的不同效应物（ERBB 2突变， EGFR扩增、NF 1突变和其他）在疾病后收集的ESR 1-野生型乳腺癌中 抗雌激素治疗的进展。这一建议是基于一个假设，即最近的进展， 无细胞DNA（cfDNA）的测序方法和分析可以前瞻性地识别分子改变 使乳腺癌患者对激素治疗产生耐药性， 与ER一起可以预防或延迟耐药克隆的出现。三个具体目标是 提出了在目标1中，在乳腺癌患者治疗前和治疗期间，从乳腺癌患者收集配对的肿瘤样品和cfDNA。 治疗和激素治疗的疾病进展时将用于定义景观， 在治疗的选择性压力下出现的分子变化的时间。我们的初步数据显示 ERBB 2突变是对激素治疗的内在和获得性抗性的机制。我们有 还发现HER激酶抑制剂来那替尼可以诱导有限的深刻的治疗反应， 通过ER活性的诱导和随后的耐药性的出现。因此，在目标2中，我们将使用 配对的治疗前和疾病进展肿瘤活检，在治疗期间定期收集cfDNA。 来那替尼单药治疗或与ER降解剂氟维司群联合治疗，以及工程化等基因模型， 患者来源的异种移植物，以鉴定和验证对这些治疗剂的抗性机制。 最后，我们的基因组分析在以下收集的约10%的肿瘤中鉴定了RAS/ERK通路的改变： 激素治疗的疾病进展。在目标3中，我们将探讨这一发现的功能意义 并寻求开发治疗策略，以克服这种分子水平上的激素治疗抗性， 定义人口。该项目的长期目标是开发ER+乳腺癌的治疗策略。 通过对肿瘤演变的实时、非侵入性分子监测来指导癌症。拟议的工作还将 产生有价值的HER 2突变型和NF 1突变型ER+乳腺癌的临床前模型， 未来的研究，以评估有前途的新的治疗方法，这些分子定义的人群。

项目成果

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: Clinical cancer research : an official journal of the American Association for Cancer Research

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: Nature communications
• 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

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: Annals of oncology : official journal of the European Society for Medical Oncology
• 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

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: JCO precision oncology
• 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

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: Genome medicine
• 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