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（由申请人提供）：靶向肿瘤血管生成必需途径的新疗法对肿瘤生长和转移的治疗具有重要意义。fda批准的抗血管生成药物，如抑制VEGF信号传导的贝伐单抗，已经产生了不同的结果。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。内啡肽是一种转化生长因子-ß （TGF-ß）共受体，在抗血管生成治疗中成为一种独特的靶点。内啡肽是：1)正常血管生成和肿瘤诱导血管生成所必需的；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是一种人源化内激素单克隆抗体（mAb），目前正处于I/II期临床试验中，用于治疗晚期实体癌或转移性癌。虽然早期的报道表明TRC105可以改善肿瘤反应，并且具有不同于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，尽管最近取得了进展，但TRC105和相关内啡肽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，它不依赖于细胞生长抑制或凋亡。相反，TRC105严重改变TGF-ß信号传导至Smad通路的关键平衡，损害内皮迁移，促进内啡肽脱落，产生循环抗血管生成因子（可溶性内啡肽）。基于我们的初步发现，我们将研究潜在的机制，评估其他内啡肽靶向单克隆抗体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-ß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，并在体内验证关键机制。总之，这些研究将为内啡肽靶向治疗提供第一个分子和细胞数据，确定新的干预药理学靶点，并帮助制定新的抗血管生成治疗策略。