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

• 批准号: 10249513
• 负责人: Sabine M Brouxhon
• 金额: $ 33.39万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249513
• 关键词: sEcad; novel; target; therapy; IGF

 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.

 描述（由申请人提供）：在过去的十年中，乳腺肿瘤学最显着的进展是 FDA 批准针对人类表皮生长因子受体（HER1 和 HER2）的靶向疗法以及针对激素受体阳性疾病的疗法。与辅助化疗相结合，曲妥珠单抗（抗 HER2 抗体）或他莫昔芬（激素疗法）等药物可显着减少转移性患者的复发并提高无病生存率然而，尽管最初有积极反应，但大多数患者表现出耐药性，导致治疗一年内胰岛素样生长因子 1 受体 (IGF-1R) 及其相关下游信号的表达增加和过度激活。因此，识别调节 IGF-1R 信号传导的新靶点和抗肿瘤药物至关重要。最近发现可溶性 E-钙粘蛋白（称为 sEcad）是一种新型致癌靶点，在人类乳腺癌中选择性增加，此外，我们还发现 sEcad 通过激活许多此类耐药途径来发挥其致瘤作用（增强增殖、迁移和侵袭）。 ，包括 IGF-1R 和下游 MAPK-PI3K/Akt/mTOR-IAP 信号传导 更重要的是，使用纯化的 IGF-1R 全感受器，我们是首先发现 sEcad 作为 IGF-1R 的真正配体，并且在其天然配体 IGF-1 存在的情况下协同增加 IGF-1R 磷酸化。此外，我们有证据表明 sEcad 与高亲和力 HER 和 IGF-1R 具有协同作用。配体IGF1和EGF在体外促进癌细胞增殖、迁移和侵袭，并在体内充当异种移植肿瘤的致癌驱动因素。此外，我们最近测试了针对 sEcad 的区域特异性抗体，该抗体通过直接诱导肿瘤细胞死亡（凋亡和坏死）成功抑制 HER2+ 和激素受体阳性乳腺癌。 -在曲妥珠单抗耐药的乳腺癌异种移植物中调节 IGF-1R、HER 和 MAPK-PI3K/Akt/mTOR-IAP 轴。内源性过度表达 IGF-1R）和 MMTV-PyMT 小鼠，我们的研究表明，sEcad 的靶向抑制通过抑制增殖和诱导细胞死亡成功地减轻了肿瘤负荷，与体内研究结果一致，这种靶向治疗抑制了增殖并直接诱导细胞凋亡和坏死。在激素受体阳性和曲妥珠单抗耐药的乳腺癌细胞中，在正常细胞中没有表现出任何脱靶细胞毒性作用。在这项转化研究中，我们组建了一支出色的研究团队来： 1) 从生物化学和生物物理角度表征 sEcad-IGF-1R 相互作用；2) 确定 sEcad 的靶向抑制是否会在体外和体内抑制表达 IGF-1R 的乳腺癌；3) 了解抗体如何发挥下调作用的机制。 IGF-1R 轴；4) 进行啮齿动物功效、PK/PD 研究和脱靶效应评估，尽管针对 IGF-1R 的单克隆抗体已给出。临床试验的结果好坏参半，这些抗 sEcad 抗体可能代表完全不同类别的 IGF1R 抑制剂，具有非常独特和创新的靶向机制。