Wound Angiogenesis as a Biomarker for Tumor Angiogenesis

描述（由申请人提供）：本提案的目标是通过1)开发基于组织的生物标志物来指导抗血管生成药物的开发，以及2)开发和指导初级临床研究人员来支持创新的以患者为导向的转化研究。一项针对转移性结直肠癌患者的贝伐单抗III期临床试验证实了抗vegf治疗的重要性。然而，贝伐单抗可能有副作用，如胃肠道穿孔、围手术期伤口愈合并发症和动脉血管事件的风险增加。这些毒性可能与VEGF在伤口愈合中的作用有关。肿瘤和伤口中的血管生成反应利用相似的细胞、基质和生长因子成分。此外，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伤口愈合的影响，我们开发了一种安全方便的皮肤伤口血管生成试验。基于临床前耐药机制、贝伐单抗在临床中的疗效和毒性特征，以及我们初步的临床前和临床数据，我们将使用治疗前和治疗中配对的肿瘤和伤口活检来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vegf治疗将1)抑制VEGFR2磷酸化，2)抑制新生血管；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；5)上调特定血管生成基因表达谱。我们假设这些效应在肿瘤和伤口中都是高度相关的。该项目将确定伤口血管生成是否可以作为抗vegf治疗的基于临床机制的生物标志物。这些研究将确定抗vegf治疗在肿瘤和伤口中的哪些作用是相似的，哪些是不同的，重点是敏感性、毒性和可靶向的耐药性机制。这项工作有可能提高这类新型药物的安全性和有效性。

DESCRIPTION (provided by applicant): The goal of this proposal is to support innovative patient oriented translational research through 1) developing tissue based biomarkers to guide the development of anti-angiogenesis drugs, and 2) development and mentoring of junior clinical researchers. The importance of anti-VEGF therapy has been validated in a phase III clinical trial of bevacizumab in patients with 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. These toxicities may be related to the role of VEGF in wound healing. Angiogenic responses in tumors and wounds utilize similar cellular, matrix, and growth factor components. Also, wound healing gene expression profiles are conserved between granulation tissue and multiple tumor types. To exploit these similarities and understand the effects of angiogenesis inhibitors on wound healing, we have developed a safe and convenient 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, we will use paired pre- and on- treatment tumor and wound biopsies to 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. We hypothesize that these effects will be highly correlated in both tumors and wounds. This project 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. In the context of this work, junior investigators will be trained in clinical research related to anti-angiogenesis agents. Trainees will have specific educational and research experiences, including the development and oversight of several biomarker studies.