Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity

摘要 抗血管内皮生长因子治疗的临床重要性最近被证实为阳性的III期结果 贝伐单抗治疗转移性结直肠癌。然而，贝伐单抗可能有副作用，如增加 胃肠道穿孔、围手术期伤口愈合并发症和动脉血管事件的风险。所有这些都是 其毒性可能与血管内皮生长因子在伤口愈合生物学中的作用有关。 肿瘤和伤口中的血管生成反应利用非常相似的细胞、基质和生长因子 肉芽组织和创伤愈合组织之间的成分和伤口愈合基因表达谱是保守的 多种肿瘤类型。利用这些相似之处并了解血管生成抑制剂对 为了促进创面愈合，我们建立了一种安全、简便的临床真皮创面血管生成检测方法。基座 根据临床前耐药机制，贝伐单抗的临床疗效和毒副作用，以及我们的 初步的临床前和临床数据，并使用成对的治疗前和治疗后肿瘤和伤口活检，我们 将检验贝伐单抗治疗将有以下分子和生理作用的假设 对患者的肿瘤和伤口都有影响。抗血管内皮生长因子治疗将(1)抑制血管内皮生长因子受体2 磷酸化，(2)抑制新生血管；(3)上调代偿性的血管内皮生长因子配体和受体；(4) 上调代偿性非血管内皮生长因子；以及(5)上调特异性血管生成基因 表达配置文件。最后，我们假设这些效应在肿瘤和 伤口。 综上所述，这项工作将确定伤口血管生成是否可以作为临床机制的基础 抗血管内皮生长因子治疗的生物标记物。这些研究将确定抗血管内皮生长因子治疗在 肿瘤和伤口既相似又不同，侧重于敏感性、毒性和耐药性的机制。 都是有针对性的。这项工作有可能提高这种新型药物的安全性和有效性。 毒品。 我；‘

Abstract The clinical importance of anti-VEGF therapy has recently been validated with the positive phase III results of bevacizumab in metastatic colorectal cancer. However, bevacizumab may have side effects such as increased risks of GI perforation, peri-operative wound healing complications, and arterial vascular events. All of these toxicities may be related to the role of VEGF in wound healing biology. Angiogenic responses in tumors and wounds utilize very similar cellular, matrix, and growth factor components and wound healing gene expression profiles are conserved between granulation tissue and multiple tumor types. To exploit these similarities and to understand the effects of angiogenesis inhibitors on wound healing, we have developed a safe and convenient clinical dermal wound angiogenesis assay. Based upon preclincial resistance mechanisms, the efficacy and toxicity profile of bevacizumab in the clinic, and our preliminary preclinical and clinical data, and using paired pre and on treatment tumor and wound biopsies, we will test the hypothesis that bevacizumab treatment will have the following molecular andphysiological consequences in both tumors and wounds in patients. Anti-VEGF therapy will (1) inhibit VEGFR2 phosphorylation, (2) inhibit neovascularization; 3) upregulate compensatory VEGF ligands and receptors; (4) uregulate compensatory non-VEGF angiogenic factors; and (5) upregulate specific angiogenic gene expression profiles. Lastly, we hypothesize that these effects will be highly correlated in both tumors and wounds. Taken together, this work will establish whether wound angiogenesis can serve as a clinical mechanism-based biomarker for anti-VEGF therapies. These studies will determine which effects of anti-VEGF therapy in tumors and wounds are similar and distinct, with a focus on mechanisms of sensitivity, toxicity, and resistance that are targetable. This work has the potential to improve both the safety and efficacy of this novel class of drugs. I; '