NEW CLINICAL BIOMARKER FOR CANCER--WOUND ANGIOGENESIS

肿瘤血管生成在肿瘤生长和转移中起着重要作用。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，由于这些药物可能具有最小的毒性，并且可能诱导肿瘤休眠或延长稳定疾病而不是肿瘤缩小，因此在进行大型III期研究之前，尚不清楚如何确定这些药物和所选择的剂量是否实际上具有生物活性。本提案的总体目标是在临床环境中评估一种新的、有前途的血管生成替代生物标志物，该标志物在技术上直接且与生物学相关——皮肤伤口血管生成测定。该试验利用4mm穿孔活检，产生强大的血管生成刺激，也可以清晰地看到新生血管生长到真皮层。在两周的时间里，通过直接显微镜和扫描激光多普勒测量新生血管中的微血管血液，无创地跟踪增殖的新血管。这种方法已经在一项健康志愿者的研究中得到了评估；它似乎具有很好的耐受性和高度可重复性。这个实验基于四个原则。首先，伤口血管生成与肿瘤血管生成受基本相同的因素和途径调控。其次，该分析提供了药物抗血管生成作用的全局读数，而不是仅分析一种特定途径。这一信息在帮助解剖和分析多种血管生成调控途径方面可能特别有用，这些途径可能被特定的抗血管生成药物改变。第三，抗血管生成药物最可能的毒性可能是改变伤口愈合或由于毛细血管易碎性增加而增加出血风险。这些影响也可以用这种方法检测到。最后，该检测在临床环境中实用且方便，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)在抗血管生成药物的临床I、II和III期试验中评估这种新型生物标志物检测的可行性和耐受性。2)利用这种新的生物标志物测定方法定量测定有前途的抗血管生成药物的抗血管生成作用。3)利用新型生物标志物法评价药物剂量、药代动力学参数与抗血管生成作用的关系。4)评估健康志愿者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.