Mechanism of endoglin-targeted anticancer therapy

内皮糖蛋白靶向抗癌治疗机制

• 批准号: 9245653
• 负责人: Nam Y Lee
• 金额: $ 11.94万
• 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 2017-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245653
• 关键词: Adverse effects; Angiogenesis Inhibitors; Apoptosis; Binding; Biological Markers; Biophysics; Blood Vessels; Cell membrane; Characteristics; Cleaved cell; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complement Factor B; Complex; Data; Diagnostic; Disseminated Malignant Neoplasm; Dose; Drug-sensitive; Endoglin; Endothelial Cells; Engineering; Epitopes; Equilibrium; FDA approved; Genetic Transcription; Gold; Human; Immediate-Early Genes; Immunoconjugates; Impairment; In Vitro; Intervention; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Pathway interactions; Pharmacology; 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; Tumor Markers; Vascular Endothelial Growth Factors; Vascular remodeling; Vegf Inhibitor; angiogenesis; base; bevacizumab; biophysical analysis; bone morphogenetic protein 9; cancer therapy; cell growth; cell type; clinical application; humanized monoclonal antibodies; improved; in vivo; inhibiting antibody; innovation; interdisciplinary approach; interest; migration; new therapeutic target; novel; novel therapeutics; prognostic; public health relevance; receptor; response; selective expression; targeted biomarker; targeted treatment; transcription factor; 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（由适用提供）：针对肿瘤血管生成必不可少的靶向途径的新疗法在治疗肿瘤生长和转移方面具有重大兴趣。 FDA批准的抗血管生成剂，例如抑制VEGF信号的贝伐单抗已产生不同的结果。虽然抗VEGF疗法在抑制肿瘤血管方面非常有效，但最近的报道表明，长期治疗可能会产生严重的毒性或导致耐药性的发展。 Endoglin是一种转化的生长因子 - ß（TGF-ß）共受体，它成为抗血管生成疗法的独特靶标。内形是：1）正常和肿瘤诱导的血管生成所必需的； 2）肿瘤血管的黄金标准生物标志物； 3）与肿瘤进展，存活率和转移密切相关。 TRC105是目前正在I/II阶段试验中用于治疗晚期固体或转移性癌症的人源化内尾单克隆抗体（MAB）。虽然早期报告表明TRC105改善了肿瘤反应，并且具有与VEGF抑制剂不同的安全机制，但其长期有效性（即灵敏度，耐药性和副作用）仍有待确定。此外，最近的进步是TRC105和相关内og抑制肿瘤血管的基本机制，这是差的理解。我们的初步研究揭示了TRC105独特的抗血管生成特性，这些特性与细胞增长抑制或凋亡无关。取而代之的是，TRC105批判性地改变了TGF-ß信号传导对SMAD途径的临界平衡，损害内皮迁移，并促进内og脱落以产生循环的抗血管生成因子（可溶性内生元）。根据我们的初步发现，我们将研究潜在的机制，评估其他针对性的MAB，以实现与表位相关的不同效果，并测试与贝伐单抗联合治疗的效率提高。我们将采用包括TGF-ß和VEGF信号传导PCR阵列在内的多学科方法来识别新型药物敏感靶标和生物标志物，创新的生物物理研究，以表征重要的AB诱导的配体结合特性，并在体内验证关键机制。总之，这些研究将提供第一个分子和细胞数据，用于靶向内聚细分靶向疗法，确定干预的新药物靶标，并帮助制定抗血管生成疗法的新策略。