Mechanism of endoglin-targeted anticancer therapy

描述（由申请人提供）：针对肿瘤血管生成必需途径的新疗法在肿瘤生长和转移的治疗中具有重要意义。 FDA 批准的抗血管生成药物（例如抑制 VEGF 信号传导的贝伐单抗）已产生不同的结果。虽然抗 VEGF 疗法在抑制肿瘤脉管系统方面非常有效，但最近的报告表明，长期治疗可能会产生严重的毒性或导致耐药性的产生。内皮糖蛋白是一种转化生长因子-β (TGF-β) 辅助受体，正在成为抗血管生成治疗中的独特靶点。内皮糖蛋白是： 1) 正常和肿瘤诱导的血管生成都需要； 2）肿瘤血管系统的金标准生物标志物； 3）与肿瘤进展、存活率和转移密切相关。 TRC105是一种人源化内皮糖蛋白单克隆抗体（mAb），目前正在进行 I/II 期试验，用于治疗晚期实体癌或转移性癌症。虽然早期报告表明 TRC105 可以改善肿瘤反应，并具有与 VEGF 抑制剂不同的安全机制，但其长期疗效（即敏感性、耐药性和副作用）仍有待确定。此外，尽管最近取得了进展，但 TRC105 和相关内皮因子单克隆抗体抑制肿瘤脉管系统的基本机制仍知之甚少。我们的初步研究揭示了 TRC105 独特的抗血管生成特性，该特性与细胞生长抑制或细胞凋亡无关。相反，TRC105 严重改变了 TGF-β 信号传导至 Smad 通路的关键平衡，损害内皮细胞迁移，并促进内皮糖蛋白脱落以产生循环抗血管生成因子（可溶性内皮糖蛋白）。根据我们的初步发现，我们将研究潜在的机制，评估其他内皮糖蛋白靶向单克隆抗体的独特表位相关效应，并测试与贝伐单抗联合治疗的增强疗效。我们将采用多学科方法，包括 TGF-β 和 VEGF 信号 PCR 阵列来识别新的药物敏感靶点和生物标志物，创新的生物物理研究来表征重要的 Ab 诱导的配体结合特征，并验证体内的关键机制。这些研究将为内皮糖蛋白靶向治疗提供第一批分子和细胞数据，确定新的干预药理学靶点，并帮助开发抗血管生成治疗的新策略。

DESCRIPTION (provided by applicant): New therapeutics that target pathways essential for tumor angiogenesis are of significant interest in the treatment of tumor growth and metastasis. FDA-approved antiangiogenic agents such as bevacizumab that inhibit VEGF signaling have yielded varying results. While anti-VEGF therapies can be quite effective at suppressing tumor vasculatures, recent reports suggest that long-term treatment may yield serious toxicity or result in development of resistance. Endoglin is a transforming growth factor-ß (TGF-ß) co-receptor that is emerging as a unique target in antiangiogenic therapy. Endoglin is: 1) required for both normal and tumor- induced angiogenesis; 2) the gold standard biomarker of tumor vasculatures; and 3) strongly correlated with tumor progression, survival rate, and metastases. TRC105 is a humanized endoglin monoclonal antibody (mAb) currently in phase I/II trials for treatment of advanced solid or metastatic cancer. While early reports indicate that TRC105 improves tumor response and has a safety mechanism distinct from VEGF inhibitors, its long-term efficacy (i.e. sensitivity, resistance, and side effects) remains to be determined. Moreover, despite recent advances, the fundamental mechanism by which TRC105 and related endoglin mAbs inhibit tumor vasculatures is poorly understood. Our preliminary studies reveal unique antiangiogenic properties of TRC105 that are independent of cell-growth inhibition or apoptosis. Instead, TRC105 critically alters the critical balance of TGF-ß signaling to the Smad pathways, impairs endothelial migration, and promotes endoglin shedding to produce a circulating antiangiogenic factor (soluble endoglin). Based on our initial findings, we will investigate the underlying mechanisms, evaluate other endoglin-targeting mAbs for distinct epitope-related effects, and test for enhanced efficacy in combination therapy with bevacizumab. We will employ multidisciplinary approaches including TGF-ß and VEGF signaling PCR arrays to identify novel drug-sensitive targets and biomarkers, innovative biophysical studies to characterize important Ab-induced ligand binding characteristics, and validate the key mechanisms in vivo. Together, these studies will provide the first molecular and cellular data for endoglin-targeting therapies, identify new pharmacological targets for intervention, and help develop new strategies for antiangiogenic therapies.