NEW CLINICAL BIOMARKER FOR CANCER--WOUND ANGIOGENESIS

近来研究表明，肿瘤血管生成在肿瘤生长和转移中起重要作用。血管生成抑制剂是一类很有前途的新型药物，在治疗人类癌症和其他疾病方面具有巨大的潜力。然而，由于这些药物的毒性可能很小，可能会导致肿瘤休眠或长期稳定的疾病，而不是肿瘤缩小，因此在致力于大型III期研究之前，尚不清楚如何确定这些药物和选定的剂量是否真的具有生物活性。这项建议的总体目标是在临床环境中评估一种新的、有前景的、技术简单且具有生物学相关性的血管生成替代生物标记物--皮肤伤口血管生成试验。该方法采用4 mm穿孔活检，可产生强大的血管生成刺激，并可清晰地显示真皮内新血管的生长情况。通过直接显微镜和扫描激光多普勒对增殖的新生血管进行为期两周的无创追踪，扫描激光多普勒测量新生血管中的微血管血液。这项测试已经在一项健康志愿者的研究中进行了评估；它似乎具有很好的耐受性和高度的重复性。这一分析基于四个原则。首先，伤口血管生成受到与肿瘤血管生成调控基本相同的因素和途径的调控。其次，这种分析提供了一种药物抗血管生成作用的全球读数，而不是只对一种特定途径的分析。这些信息可能在帮助解剖和分析可能被特定的抗血管生成剂改变的多个血管生成调节通路方面特别有用。第三，抗血管生成药物最有可能的毒性可能是改变伤口愈合或由于增加毛细血管脆性而增加出血风险。这些影响也应该可以用这种检测方法检测出来。最后，该方法实用、方便，可用于临床环境，这是任何替代生物标志物检测的关键要求。本研究的具体目标是：1)评估这种新的生物标志物在抗血管生成药物临床I、II和III期试验中的可行性和耐受性。2)用这一新的生物标志物定量检测有前景的抗血管生成药物的抗血管生成作用。3)应用这一新的生物标志物评价药物剂量与药代动力学参数和抗血管生成效应的关系。4)在健康志愿者中评估这一正常伤口血管生成试验的几种潜在改进，并将这些改进纳入涉及新型抗血管生成药物的患者研究中。

Tumor angiogenesis has recently been shown to play essential role in tumor growth and metastases. Angiogenesis inhibitors are a promising new class of drugs with great potential for the treatment of human cancers, as well as other diseases. However, since these drugs may have minimal toxicities and may induce tumor dormancy or prolonged stable disease rather than tumor shrinkage, it is unclear how to determine whether these agents and the selected doses are in fact biologically active before committing to large phase III studies. The overall goal of this proposal is to evaluate in the clinical setting a novel and promising surrogate bio-marker of angiogenesis that is both technically straightforward and biologically relevant-- the skin wound angiogenesis assay. This assay utilizes a 4mm punch biopsy, which produces a potent angiogenic stimulus and also allows clear visualization of new vessels growing into the dermis. The proliferating neo- vasculature is followed non-invasively over a two week period by direct microscopy and by scanning laser Doppler, which measures micro-vessel blood in the newly developing vasculature. This assay has been evaluated in a study of healthy volunteers; it appears to be very well tolerated and is highly reproducible. This assay is based upon four principles. First, wound angiogenesis is regulated by fundamentally the same factors and pathways that regulate tumor angiogenesis. Second, this assay provides a global readout of a drug's anti-angiogenic effect rather than an analysis of only one specific pathway. This information may be particularly useful in helping to dissect and analyze multiple angiogenesis regulatory pathways that may be altered by a specific anti-angiogenic agent. Third, the most likely toxicity of anti-angiogenesis agents may be altered wound healing or a greater bleeding risk due to increased capillary fragility. These effects should also be detectable with this assay. Lastly, this assay is practical and convenient to use in the clinical setting, which is a critical requirement for any surrogate bio-marker assay. The specific goals of this study are: 1) To evaluate the feasibility and tolerability of this novel bio-marker assay in clinical phase I, II, and III trials of anti-angiogenesis agents. 2) To quantitate the anti-angiogenic effect of promising anti- angiogenesis agents using this novel biomarker assay. 3) To evaluate the relationship between drug dose and pharmacokinetic parameters and anti-angiogenic effect using this novel biomarker assay. 4) To evaluate several potential refinements of this normal wound angiogenesis assay in healthy volunteers, and incorporate these refinements in to patient studies involving novel anti-angiogenesis agents.