Microenvironmental FGF2-mediated resistance to anti-estrogen and PI3K/mTOR pathway therapeutics in ER+ breast cancer

微环境 FGF2 介导的 ER 乳腺癌对抗雌激素和 PI3K/mTOR 通路治疗的耐药性

基本信息

批准号：
9897496
负责人：
Kevin Shee
金额：
$ 2.77万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2020-06-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897496
关键词：
1-Phosphatidylinositol 3-Kinase Adipocytes Adjuvant Antibodies Antiestrogen Therapy Apoptosis Aromatase Inhibitors Bioinformatics Breast Breast Adenocarcinoma Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Cell Cycle Arrest Cell Line Cells Cellular Structures Clinical Clinical Management Clinical Trials Combined Modality Therapy DNA Damage Data Dependence Disease Disease Resistance Disseminated Malignant Neoplasm Drug Targeting Drug resistance Endothelial Cells Estrogen Antagonists Estrogen Receptor alpha Estrogen Therapy Estrogen receptor positive Estrogens Exhibits Extracellular Matrix FGF2 gene FRAP1 gene Fibroblast Growth Factor Receptors Fibroblasts Fulvestrant Gene Expression Growth Factor High Prevalence Immune Immunoblotting In Vitro Individual Laboratories Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Mediator of activation protein Metastatic Neoplasm to the Bone Modeling Mus Neoplasm Metastasis Normal tissue morphology Outcome Pathway interactions Patient-derived xenograft models of breast cancer Patients Phenotype Pre-Clinical Model Prognostic Marker Protein Isoforms Proteins Recurrence Recurrent disease Regimen Resistance Resistance development Role SDZ RAD Signal Transduction Specificity Tamoxifen Testing Therapeutic Tissues Treatment Efficacy Xenograft Model advanced disease bioinformatics pipeline bone breast cancer progression cancer recurrence combat cytokine follow-up genetic approach high throughput screening human tissue improved in vivo inhibitor/antagonist kinase inhibitor malignant breast neoplasm mouse model novel phosphoproteomics prevent protein expression recruit resistance mechanism response success targeted treatment therapeutic target therapy resistant tumor tumor microenvironment tumor progression

项目摘要

Project Summary Despite the clinical success of anti-estrogen therapies for the treatment of patients with estrogen receptor- positive (ER+) breast cancer, recurrences occur in ~1/3 of patients treated in the adjuvant setting and almost all patients treated in the metastatic setting. The phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway has been implicated in anti-estrogen resistance, and drugs targeting these pathways are approved or in clinical trials. Unfortunately, nearly all ER+ breast cancers progress on these therapies as well. The high prevalence of disease recurrence in patients, despite dramatic treatment efficacy in preclinical models, led us to postulate that components of the tumor microenvironment significantly contribute to resistance to anti-estrogens and PI3K/mTOR inhibitors in ER+ breast cancer. Using a novel, microenvironment-focused approach combining high-throughput screening and bioinformatics, we uncovered fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to both anti-estrogens and PI3K/mTOR inhibitors that is highly expressed in normal tissues relevant to the microenvironments of ER+ breast cancer. FGF2 rescues cells from treatment-induced apoptosis and cell cycle arrest, and rescue is abrogated by an FGF2-specific antibody or a kinase inhibitor targeting all four FGF receptors (FGFRs). We hypothesize that FGF2 mediates resistance to both anti-estrogens and PI3K/mTOR inhibitors, alone and in combination, through pathways downstream of FGFRs that converge on signaling nodes that modulate cell fate, and that resistance can be abrogated with FGF2-targeted therapeutics in settings of both primary and metastatic ER+ breast cancer. Specific Aim 1 will determine the precise mechanism(s) of FGF2-mediated rescue from anti- estrogens and PI3K/mTOR inhibitors, which may provide novel tumor-specific therapeutic targets necessary for the resistance phenotype. FGFR isoform specificity will be determined using genetic approaches, and identification of downstream signaling networks involved in FGF2-mediated resistance will be achieved using immunoblotting and phosphoproteomics. Specific Aim 2 will use 3 microenvironmentally-relevant tumor models of ER+ breast cancer to assess whether targeting FGF2 enhances response to anti-estrogens and PI3K inhibitors. FGF2 is highly expressed in mammary tissue, bone, and primary fibroblasts, so we will utilize models of these tumor microenvironments: 1) an orthotopic primary breast cancer patient-derived xenograft (PDX) model, 2) a bone metastasis cell line-derived xenograft model developed by the applicant, and 3) a murine ER+ mammary adenocarcinoma model that heavily recruits host-derived FGF2-secreting fibroblasts. Through these studies, we will uncover potentially druggable protein targets that are required for FGF2- mediated drug resistance, and define the appropriate clinical setting for FGF2-directed therapy for ER+ breast cancer. These advances will improve therapeutic strategies to abrogate and prevent resistance to anti- estrogens and PI3K/mTOR-directed therapies in patients with ER+ breast cancer.

项目摘要尽管抗雌激素疗法在治疗雌激素受体的患者方面取得了成功阳性（ER+）乳腺癌，在佐剂环境中接受治疗的患者中发生复发，几乎所有在转移性环境中接受治疗的患者。磷脂酰肌醇3-激酶（PI3K）/机械目标雷帕霉素（MTOR）途径与抗雌激素的耐药性有关，针对这些途径途径获得批准或临床试验。不幸的是，几乎所有的ER+乳腺癌都在这些方面进展疗法也是如此。尽管患者的疾病复发率很高，尽管治疗效果很大临床前模型，使我们假设肿瘤微环境的成分显着贡献在ER+乳腺癌中抗性抗雌激素和PI3K/mTOR抑制剂。使用小说，相结合高通量筛查和生物信息学的微环境方法，我们发现了成纤维细胞生长因子2（FGF2）作为对抗雌激素和PI3K/MTOR的有效介质在与ER+乳腺癌的微环境有关的正常组织中高度表达的抑制剂。 FGF2从治疗引起的细胞凋亡和细胞周期停滞中拯救细胞，救援被一个 FGF2特异性抗体或靶向所有四种FGF受体（FGFR）的激酶抑制剂。我们假设这一点 FGF2介导对抗雌激素和PI3K/mTOR抑制剂的抗性，单独和组合，通过FGFR下游的途径，在调节细胞命运的信号节点上收敛，并在原发性和转移性ER+的设置中，可以用FGF2靶向的治疗方法消除耐药性乳腺癌。特定的目标1将确定FGF2介导的抗抗物的精确机制雌激素和PI3K/MTOR抑制剂，可能提供新颖的肿瘤特异性治疗靶标对于电阻表型。 FGFR同工型特异性将使用遗传方法确定，并且使用FGF2介导的电阻涉及的下游信号网络的识别将使用免疫印迹和磷酸化蛋白质组学。特定的目标2将使用3个微环境与相关的肿瘤模型 ER+乳腺癌的靶向FGF2是否增强了对抗雌激素和PI3K的反应抑制剂。 FGF2在乳腺组织，骨骼和原发性成纤维细胞中高度表达，因此我们将利用这些肿瘤微环境的模型：1）原位的原发性乳腺癌患者衍生的异种移植物（PDX）模型，2）由申请人开发的骨转移细胞系衍生的异种移植模型，3）A 鼠ER+乳腺癌模型，该模型大量招募了宿主衍生的FGF2分泌成纤维细胞。通过这些研究，我们将发现FGF2-所需的潜在可毒蛋白靶标介导的耐药性，并为FGF2定向治疗的ER+乳房定义适当的临床环境癌症。这些进步将改善消除和防止抗抗药性的治疗策略 ER+乳腺癌患者的雌激素和PI3K/MTOR指导的疗法。