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)：针对肿瘤血管生成所必需的通路的新疗法在治疗肿瘤生长和转移方面具有重要意义。FDA批准的抗血管生成药物，如贝伐单抗，抑制血管内皮生长因子信号转导，产生了不同的结果。虽然抗血管内皮生长因子治疗可以非常有效地抑制肿瘤血管，但最近的报告表明，长期治疗可能会产生严重的毒性或导致耐药性的产生。Endoglin是一种转化生长因子(TGF)联合受体，正在成为抗血管生成治疗的独特靶点。Endoglin是：1)正常和肿瘤诱导的血管生成所必需的；2)肿瘤血管的金标准生物标志物；3)与肿瘤进展、生存率和转移密切相关。TRC105是一种人源化的endoglin单抗，目前正处于I/II期试验，用于治疗晚期实体癌或转移性癌症。虽然早期的报道表明，TRC105可以改善肿瘤反应，并且具有与血管内皮生长因子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和相关的endoglin单抗抑制肿瘤血管的基本机制尚不清楚。我们的初步研究揭示了TRC105独特的抗血管生成特性，该特性独立于细胞生长抑制或细胞凋亡。相反，TRC105严重改变了Smad通路中的转化生长因子-β信号的关键平衡，损害了内皮细胞的迁移，并促进了endoglin的脱落，从而产生了一种循环中的抗血管生成因子(可溶性endoglin)。基于我们的初步发现，我们将研究潜在的机制，评估其他内源性靶向单抗的不同表位相关效应，并测试与贝伐单抗联合治疗的增强疗效。我们将使用多学科方法，包括转化生长因子和血管内皮生长因子信号聚合酶链式反应阵列，以确定新的药物敏感靶点和生物标记物，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征，并验证体内的关键机制。总之，这些研究将为内源性靶向治疗提供第一批分子和细胞数据，确定干预的新药理学靶点，并帮助开发抗血管生成治疗的新策略。