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.

项目概要尽管抗雌激素疗法在治疗雌激素受体患者方面取得了临床成功，阳性 (ER+) 乳腺癌，约 1/3 接受辅助治疗的患者会出现复发，并且几乎所有在转移环境中接受治疗的患者。磷脂酰肌醇 3-激酶 (PI3K)/机制靶点雷帕霉素 (mTOR) 通路与抗雌激素耐药性有关，针对这些通路的药物途径已获批准或正在进行临床试验。不幸的是，几乎所有 ER+ 乳腺癌都在这些方面进展疗法也是如此。尽管治疗效果显着，但患者疾病复发率很高临床前模型使我们假设肿瘤微环境的组成部分显着贡献 ER+ 乳腺癌对抗雌激素和 PI3K/mTOR 抑制剂的耐药性。借用一本小说，我们发现，结合高通量筛选和生物信息学的以微环境为中心的方法成纤维细胞生长因子 2 (FGF2) 作为抗雌激素和 PI3K/mTOR 抗性的有效介质在与 ER+ 乳腺癌微环境相关的正常组织中高表达的抑制剂。 FGF2 将细胞从治疗诱导的细胞凋亡和细胞周期停滞中拯救出来，并且拯救被一个针对所有四种 FGF 受体 (FGFR) 的 FGF2 特异性抗体或激酶抑制剂。我们假设 FGF2 单独或联合介导抗雌激素和 PI3K/mTOR 抑制剂的耐药性，通过 FGFR 下游的通路汇聚到调节细胞命运的信号节点，并且在原发性和转移性 ER+ 的情况下，可以通过 FGF2 靶向治疗消除耐药性乳腺癌。具体目标 1 将确定 FGF2 介导的抗逆转录病毒救援的精确机制。雌激素和 PI3K/mTOR 抑制剂，可能提供新的肿瘤特异性治疗靶点对于耐药表型。 FGFR 亚型特异性将使用遗传方法确定，并且鉴定参与 FGF2 介导的耐药性的下游信号网络将通过以下方法实现：免疫印迹和磷酸蛋白质组学。具体目标 2 将使用 3 个微环境相关肿瘤模型 ER+ 乳腺癌的研究，以评估靶向 FGF2 是否增强对抗雌激素和 PI3K 的反应抑制剂。 FGF2 在乳腺组织、骨和初级成纤维细胞中高表达，因此我们将利用这些肿瘤微环境的模型：1）原位原发性乳腺癌患者来源的异种移植物 (PDX)模型，2)申请人开发的骨转移细胞系来源的异种移植模型，以及3) 小鼠 ER+ 乳腺癌模型，大量招募宿主来源的 FGF2 分泌成纤维细胞。通过这些研究，我们将发现 FGF2- 所需的潜在可药物化蛋白质靶点介导的耐药性，并确定 FGF2 定向治疗 ER+ 乳腺的适当临床环境癌症。这些进展将改进治疗策略，以消除和预防抗药性 ER+ 乳腺癌患者的雌激素和 PI3K/mTOR 导向疗法。