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

 描述(申请人提供)：在过去的十年中，乳腺肿瘤学中最重要的革命性进展是FDA批准了针对人类表皮生长因子受体(HER1和HER2)的靶向治疗以及激素受体阳性疾病的治疗。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)等药物显著减少了转移性疾病患者的复发并提高了无瘤存活率。然而，尽管最初的反应是积极的，但大多数患者表现出耐药性--使治疗在治疗一年内无效。胰岛素样生长因子1受体(IGF-1R)及其下游信号转导元件(MAPK-PI3K/Akt/mTOR-IAP)的高表达和高活性与这种从头耐药和获得性耐药有关。因此，识别调节IGF-1R信号的新靶点和抗肿瘤药物是至关重要的。我们最近发现，可溶性E-钙粘附素，称为sEcad，是一种新的致癌靶点，在人类乳腺癌中选择性增加。此外，我们还发现，sEcad通过激活许多这些耐药通路，包括IGF-1R和下游的MAPK-PI3K/Akt/mTOR-IAP信号，来发挥其致瘤作用(促进增殖、迁移和侵袭)。更重要的是，使用纯化的IGF-1R全受体，我们首次发现sECAD是IGF-1R的真正配体，并且在其天然配体存在的情况下，IGF-1协同增加IGF-1R的磷酸化。此外，我们有证据表明，sECAD与高亲和力的HER和IGF-1R配体IGF1和EGF协同作用，在体外促进癌细胞的增殖、迁移和侵袭，并在体内充当异种移植瘤的致癌驱动因素。因此，我们认为sECAD是一种有效的、创新的乳腺癌治疗靶点。此外，我们最近测试了针对sECAD的区域特异性抗体，通过下调IGF-1R、HER和MAPK-PI3K/Akt/mTOR-IAP轴，成功地通过直接诱导肿瘤细胞死亡(细胞凋亡和坏死)来抑制HER2+和激素受体阳性的乳腺癌。在曲妥珠单抗耐药的乳腺癌移植瘤(内源性过表达IGF-1R)和MMTV-PyMT小鼠中，我们的研究表明，靶向抑制sEcad成功地通过抑制增殖和诱导细胞死亡来减少肿瘤负担。与体内研究结果一致的是，这种靶向治疗抑制了激素受体阳性和曲妥珠单抗耐药的乳腺癌细胞的增殖，并直接诱导了细胞的凋亡和坏死，而在正常细胞中没有表现出任何非靶向的细胞毒效应。在这项翻译研究中，我们组建了一支出色的研究团队，以：1)从生化和生物物理角度表征sECAD-IGF-1R的相互作用；2)确定靶向抑制sECAD是否在体内外抑制表达IGF-1R的乳腺癌；3)从机制上深入了解抗体如何下调IGF-1R轴；以及4)进行啮齿动物疗效、PK/PD研究和非靶点效应评估。值得注意的是，尽管抗IGF-1R的单抗在临床试验中给出了喜忧参半的结果，但这些抗sECAD抗体潜在地代表了一类完全不同的IGF1R抑制剂，具有非常独特和创新的靶向机制。

 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.