Mechanism of endoglin-targeted anticancer therapy

内皮糖蛋白靶向抗癌治疗机制

• 批准号: 8839215
• 负责人: Nam Y Lee
• 金额: $ 31.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839215
• 关键词: Adverse effects; Angiogenesis Inhibitors; Apoptosis; Binding; Biological Markers; Blood Vessels; Cell membrane; Characteristics; Cleaved cell; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complex; Data; Diagnostic; Disseminated Malignant Neoplasm; Dose; Drug-sensitive; Endoglin; Endothelial Cells; Engineering; Epitopes; Equilibrium; FDA approved; Gold; Health; Human; Immediate-Early Genes; Immunoconjugates; In Vitro; Intervention; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Pathway interactions; Phase I/II Trial; Phosphotransferases; Plasma; Process; Production; Proliferating; Property; Receptor Signaling; Reporting; Research Proposals; Resistance; Resistance development; Role; Safety; Signal Transduction; Solid; Solid Neoplasm; Survival Rate; TGF-beta type I receptor; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Transforming Growth Factors; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Vascular remodeling; angiogenesis; base; bevacizumab; biophysical analysis; bone morphogenetic protein 9; cancer therapy; cell growth; cell type; clinical application; humanized monoclonal antibodies; improved; in vivo; inhibitor/antagonist; innovation; interdisciplinary approach; interest; migration; new therapeutic target; novel; prognostic; receptor; response; selective expression; targeted treatment; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：靶向肿瘤血管生成所必需的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批准的抑制VEGF信号传导的抗血管生成剂如贝伐单抗产生了不同的结果。虽然抗VEGF疗法可以非常有效地抑制肿瘤血管，但最近的报告表明，长期治疗可能产生严重的毒性或导致耐药性的发展。内皮糖蛋白是一种转化生长因子-β（TGF-β）共受体，正成为抗血管生成治疗的独特靶点。内皮糖蛋白是：1）正常和肿瘤诱导的血管生成所需; 2）肿瘤血管的金标准生物标志物;和3）与肿瘤进展、存活率和转移密切相关。TRC 105是一种人源化内皮糖蛋白单克隆抗体（mAb），目前处于I/II期试验中，用于治疗晚期实体瘤或转移性癌症。虽然早期的报告表明，TRC 105改善了肿瘤反应，并具有不同于VEGF抑制剂的安全机制，但其长期疗效（即敏感性、耐药性和副作用）仍有待确定。此外，尽管最近的进展，TRC 105和相关内皮糖蛋白单克隆抗体抑制肿瘤血管的基本机制知之甚少。我们的初步研究揭示了TRC 105独特的抗血管生成特性，其独立于细胞生长抑制或凋亡。相反，TRC 105严重改变TGF-β信号传导至Smad途径的关键平衡，损害内皮迁移，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）。基于我们的初步发现，我们将研究潜在的机制，评估其他内皮素靶向mAb的不同表位相关作用，并测试与贝伐单抗联合治疗的增强疗效。我们将采用多学科的方法，包括TGF-β和VEGF信号PCR阵列，以确定新的药物敏感的目标和生物标志物，创新的生物物理研究，以表征重要的抗体诱导的配体结合特性，并验证体内的关键机制。总之，这些研究将为内皮素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，并帮助开发新的抗血管生成治疗策略。