Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity

摘要 抗VEGF治疗的临床重要性最近已被证实与积极的III期结果， 贝伐单抗治疗转移性结直肠癌然而，贝伐珠单抗可能具有副作用，例如增加 GI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 毒性可能与VEGF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 组分和伤口愈合基因表达谱在肉芽组织和 多种肿瘤类型。为了利用这些相似性并了解血管生成抑制剂对 创伤愈合，我们已经开发了一种安全和方便的临床皮肤创伤血管生成测定。基于 根据临床前耐药机制，贝伐单抗在临床中的疗效和毒性特征，以及我们的 初步的临床前和临床数据，并使用配对的治疗前和治疗中的肿瘤和伤口活检，我们 将检验贝伐单抗治疗将具有以下分子和生理学效应的假设： 对患者的肿瘤和伤口都有影响。抗VEGF治疗将（1）抑制VEGFR 2 磷酸化，（2）抑制新血管形成;（3）上调代偿性VEGF配体和受体;（4） 上调代偿性非VEGF血管生成因子;和（5）上调特异性血管生成基因 表达谱。最后，我们假设这些效应在肿瘤和 伤口 总之，这项工作将建立是否伤口血管生成可以作为一个临床机制为基础的 抗VEGF治疗的生物标志物。这些研究将确定抗VEGF治疗在 肿瘤和伤口相似且不同，其敏感性、毒性和抗性机制是重点 是有针对性的这项工作有可能提高这类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; '