NEW CLINICAL BIOMARKER FOR CANCER--WOUND ANGIOGENESIS

肿瘤血管生成在肿瘤的生长和转移中起着重要作用。 血管生成抑制剂是一类有前途的新型药物，具有治疗人类癌症以及其他疾病的巨大潜力。 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长期稳定的疾病，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剂量是否具有生物活性。本提案的总体目标是在临床环境中评估一种新的和有前途的替代生物标志物的血管生成，这是技术上简单和生物学相关的-皮肤伤口血管生成测定。 该测定利用4 mm穿刺活检，其产生有效的血管生成刺激，并且还允许清楚地可视化生长到真皮中的新血管。 通过直接显微镜和扫描激光多普勒在两周时间内非侵入性地跟踪增殖的新脉管系统，所述扫描激光多普勒测量新发育的脉管系统中的微血管血液。 在一项健康志愿者研究中评价了该试验;该试验似乎耐受性良好，重现性高。该分析基于四个原则。 首先，伤口血管生成受调节肿瘤血管生成的基本相同的因子和途径调节。 其次，该测定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。 这些信息可能特别有助于剖析和分析可能被特定抗血管生成剂改变的多种血管生成调节途径。 第三，抗血管生成剂最可能的毒性可能是由于毛细血管脆性增加而改变伤口愈合或增加出血风险。 这些影响也应该是可检测的。 最后，该测定在临床环境中使用是实用和方便的，这是任何替代生物标志物测定的关键要求。本研究的具体目标是：1）评估这种新型生物标志物测定在抗血管生成剂的I、II和III期临床试验中的可行性和耐受性。2)使用这种新的生物标志物测定来定量有前途的抗血管生成剂的抗血管生成作用。 3)评价药物剂量与药代动力学参数之间的关系，并使用这种新的生物标志物测定法评价抗血管生成作用。 4)在健康志愿者中评价这种正常伤口血管生成测定的几种潜在改进，并将这些改进纳入涉及新型抗血管生成剂的患者研究中。

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.