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

 描述（由申请人提供）：在过去十年中，乳腺肿瘤学最重要的革命性进展是FDA批准了针对人表皮生长因子受体（HER 1和HER 2）的靶向治疗和针对EGFR阳性疾病的治疗。联合辅助化疗，药物如曲妥珠单抗（抗HER 2抗体）或他莫昔芬（激素疗法）可显著降低复发率，并增加转移性疾病患者的无病生存期。然而，尽管最初有积极的反应，但大多数患者表现出耐药性-使治疗在一年内无效。胰岛素样生长因子1受体（IGF-1 R）及其相关下游信号传导组分（MAPK-PI 3 K/Akt/mTOR-IAP）的表达增加和过度活化与这种从头和获得性耐药性有关。因此，鉴定调节IGF-1 R信号传导的新靶点和抑制剂至关重要。 我们最近确定了可溶性E-钙粘蛋白，称为sEcad，作为一种新的致癌目标，在人类乳腺癌中选择性增加。此外，我们发现sEcad通过激活许多这些抗性途径，包括IGF-1 R和下游MAPK-PI 3 K/Akt/mTOR-IAP信号传导，赋予其致瘤作用（增强增殖、迁移和侵袭）。更重要的是，使用纯化的IGF-1 R全受体，我们首次发现sEcad作为IGF-1 R的真正配体，并且在其天然配体IGF-1的存在下协同增加IGF-1 R磷酸化。此外，我们有证据表明sEcad与高亲和力HER和IGF-1 R配体IGF 1和EGF协同作用，以促进癌细胞增殖，迁移和体外侵袭，并在体内异种移植肿瘤中充当致癌驱动因子。因此，我们认为sEcad是乳腺癌的有效和创新的治疗靶点。 此外，我们最近测试了针对sEcad的区域特异性抗体，其通过下调IGF-1 R、HER和MAPK-PI 3 K/Akt/mTOR-IAP轴直接诱导肿瘤细胞死亡（凋亡和坏死），成功抑制HER 2+和HER 2受体阳性乳腺癌。在曲妥珠单抗耐药乳腺癌异种移植物（内源性过表达IGF-1 R）和MMTV-PyMT小鼠中，我们的研究表明，靶向抑制sEcad通过抑制增殖和诱导细胞死亡成功降低了肿瘤负荷。与体内研究结果一致，这种靶向治疗可抑制增殖，并直接诱导受体阳性和曲妥珠单抗耐药乳腺癌细胞的凋亡和坏死，而在正常细胞中未显示出任何脱靶细胞毒性效应。 在这项转化研究中，我们组建了一个杰出的研究团队：1）生化和生物药理学表征sEcad-IGF-1 R相互作用; 2）确定靶向抑制sEcad是否在体外和体内抑制IGF-1 R表达乳腺癌; 3）获得抗体如何下调IGF-1 R轴的机制见解;和4）进行啮齿动物功效、PK/PD研究和脱靶效应的评价。 值得注意的是，尽管针对IGF-1 R的单克隆抗体在临床试验中给出了混合的结果，但这些抗sEcad抗体可能代表了完全不同类别的IGF 1 R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.