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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.

项目总结