Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity

描述(申请人提供)：摘要 最近，贝伐单抗在转移性结直肠癌的III期阳性结果证实了抗血管内皮生长因子治疗的临床重要性。然而，贝伐单抗可能有副作用，如增加胃肠道穿孔的风险、围手术期伤口愈合并发症和动脉血管事件。这些毒性可能与血管内皮细胞生长因子在伤口愈合生物学中的作用有关。 肿瘤和伤口的血管生成反应利用非常相似的细胞、基质和生长因子成分，伤口愈合基因表达谱在肉芽组织和多种肿瘤类型之间是保守的。为了利用这些相似性并了解血管生成抑制剂对创面愈合的影响，我们建立了一种安全、方便的临床真皮创面血管生成检测方法。根据临床前耐药机制、贝伐单抗在临床上的疗效和毒性特征以及我们的初步临床前和临床数据，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对患者的肿瘤和伤口产生以下分子和生理后果的假设。抗血管内皮生长因子治疗将：(1)抑制VEGFR2的磷酸化；(2)抑制新生血管形成；(3)上调代偿性的VEGF配体和受体；(4)上调代偿性的非血管生成因子；(5)上调特定的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中都是高度相关的。 综上所述，这项工作将确定伤口血管生成是否可以作为抗血管内皮生长因子治疗的临床机制生物标记物。这些研究将确定抗血管内皮生长因子治疗在肿瘤和伤口中的相似和不同的作用，重点放在有针对性的敏感性、毒性和耐药性的机制上。这项工作有可能提高这类新药的安全性和有效性。

DESCRIPTION (provided by applicant): 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 preclinical 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 and physiological 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) upregulate 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.