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sEcad as a novel target and therapy for IGF-1R expressing tumors

sEcad 作为 IGF-1R 表达肿瘤的新靶点和治疗方法

基本信息

批准号：
8962751
负责人：
Sabine M Brouxhon
金额：
$ 0.57万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2015-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8962751
关键词：
Address Adjuvant Chemotherapy Affinity Antibodies Antigens Antineoplastic Agents Apoptosis Binding Biochemical Breast Breast Cancer Cell Breast Carcinogenesis Breast cancer metastasis Cell Death Cell Proliferation Cells Cetuximab Clinical Trials Development Disease Disease-Free Survival Drug Kinetics E-Cadherin EGF gene ERBB2 gene Effectiveness Endocytosis Epidermal Growth Factor Receptor Evaluation Studies Exhibits Grant Growth Growth Factor Hormone Receptor Human IGF1 gene IGF1R gene In Vitro Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Lead Ligands MAP Kinase Gene Malignant Neoplasms Mediating Modeling Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Necrosis Neoplasm Metastasis Normal Cell Oncogenic Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phosphorylation Proteins Receptor Inhibition Receptor Signaling Relapse Research Resistance Rodent Signal Transduction Tamoxifen Testing Trastuzumab Tumor Burden Woman Xenograft procedure biophysical properties cancer cell crosslink cytotoxic hormone therapy human FRAP1 protein in vivo inhibitor/antagonist innovation insight malignant breast neoplasm migration mouse model neoplastic cell novel oncology overexpression public health relevance receptor response safety testing targeted treatment therapeutic target therapy development translational study tumor tumor growth tumor xenograft tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Over the last decade, the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone-receptor-positive disease. In combination with adjuvant chemotherapy, drugs such as trastuzumab (anti-HER2 antibody) or tamoxifen (hormone therapy) have significantly reduced relapses and increased disease-free survival in patients with metastatic disease. However, despite an initial positive response, the majority of patient's exhibit resistance - rendering the therapy ineffective within one year of treatment. Increased expression and hyperactivation of the insulin-like growth factor 1 receptor (IGF-1R) and its associated downstream signaling components (MAPK-PI3K/Akt/mTOR- IAP) have been implicated in this de novo and acquired resistance. Therefore, identification of novel targets and antineoplastic agents that modulate IGF-1R signaling is paramount. We have recently identified soluble E-cadherin, termed sEcad, as a novel oncogenic target that is selectively increased in human breast cancers. Additionally, we have discovered that sEcad imparts its tumorigenic effects (enhances proliferation, migration and invasion) by activating many of these resistance pathways, including IGF-1R and downstream MAPK-PI3K/Akt/mTOR-IAP signaling. More importantly, using a purified IGF-1R holoreceptor, we are the first to discover that sEcad acts as a true ligand for IGF-1R and in the presence of its natural ligand IGF-1 synergistically increases IGF-1R phosphorylation. Furthermore, we have evidence that sEcad synergizes with the high-affinity HER and IGF-1R ligands, IGF1 and EGF, to promote cancer cell proliferation, migration and invasion in vitro and act as an oncogenic driver in xenograft tumors in vivo. Therefore, we propose that sEcad is a valid and innovative therapeutic target for breast cancer. Additionally, we have recently tested region-specific antibodies against sEcad that successfully suppressed HER2+ and hormone-receptor positive breast cancers by directly inducing tumor cell death (apoptosis and necrosis), via down-regulating the IGF-1R, HER and MAPK-PI3K/Akt/mTOR-IAP axis. In trastuzumab-resistant breast cancer xenografts (which endogenously overexpress IGF-1R) and MMTV-PyMT mice, our studies demonstrate that targeted inhibition of sEcad successfully reduced tumor burden by inhibiting proliferation and inducing cell death. Consistent with the in vivo findings, this targeted therapy inhibited proliferation and directly induced apoptosis and necrosis in hormone-receptor-positive and trastuzumab-resistant breast cancer cells, without showing any off-target cytotoxic effects in normal cells. In this translational study, we have assembled an outstanding research team to: 1) biochemically and biophysically characterize the sEcad-IGF-1R interactions; 2) determine whether targeted inhibition of sEcad suppresses IGF-1R expressing breast cancers in vitro and in vivo; 3) gain mechanistic insights into how the antibody functions to down-regulate the IGF-1R axis; and 4) perform rodent efficacy, PK/PD studies and evaluation of off-target effects. Of note, although monoclonal antibodies against IGF-1R have given mixed results in clinical trials, these anti-sEcad antibodies potentially represent a completely different class of IGF1R inhibitors, with a very unique and innovative targeting mechanism.