INTEGRATION OF ANTIANGIOGENIC THERAPY WITH RADIATION

血管生成对于许多生理和病理生理过程是至关重要的，并且血管生成抑制剂现在正在临床试验中进行评估。最近，我们通过研究肿瘤块对肿瘤生长的抑制作用，发现了血管生成抑制剂血管抑素、内皮抑素和抗血管生成抗凝血酶（aaAT）。所有这三种都来自内源性蛋白质的蛋白水解。在体内，这些药物已被用于消退各种恶性肿瘤，并可以诱导一种类型的肿瘤休眠持续的肿瘤细胞凋亡和增殖之间的动态平衡和血管生成的虚拟完全阻断。然而，临床前研究表明，在开始抗血管生成治疗后，活性的发作显著延迟，并且肿瘤通常在对治疗作出反应之前进展 即使在施用高剂量时也是如此。此外，显微镜下残留疾病在所有动物中持续存在，并且出现了内皮异质性的证据，表明血管生成抑制剂在不同毛细血管床中可能具有不同的活性。综合考虑，这些发现表明，使用抗血管生成药物作为单一疗法将不足以治疗大多数晚期癌症患者。 该项目的目标是为抗血管生成治疗与放射治疗的整合提供合理的基础。第一个具体目标是使用癌症的临床前模型来优化抗血管生成剂与放射治疗的组合。假设是，当抗血管生成剂和常规方式相结合时，它们的局限性将减少，并产生协同效应。第二个具体目标是开发和验证替代物，以监测与放射治疗联合使用时抗血管生成治疗的效果。预测早期肿瘤反应的有用替代物对于将抗血管生成治疗纳入临床实践至关重要。的 这些研究的结果将直接关系到癌症临床试验的规划。

Angiogenesis is critical for a number of physiological and pathophysiological processes and angiogenesis inhibitors are now being evaluated in clinical trials. Recently, we discovered the angiogenesis inhibitors angiostatin, endostatin, and antiangiogenic antithrombin (aaAT) by studying the inhibition of tumor growth by tumor mass. All three are derived from proteolysis of endogenous proteins. In vivo, these agents have been used to regress a wide variety of malignant tumors and can induce a type of tumor dormancy sustained by a dynamic equilibrium between tumor cell apoptosis and proliferation and a virtual complete blockade of angiogenesis. However, preclinical studies demonstrate a significant delay in the onset of activity after initiation of antiangiogenic therapy and tumors often progress before responding to treatment even when high doses are administered. Further, microscopic residual disease persists in all animals and there is emerging evidence of heterogeneity of the endothelium suggesting that angiogenesis inhibitors may have differential activity in different capillary beds. When taken together, these findings suggest that the use of antiangiogenic agents as monotherapy will not be adequate for most patients with advanced cancer. The goal of this project is to develop a rational basis for the integration of antiangiogenic therapy with radiation therapy. The first specific aim is to use preclinical models of cancer to optimize the combination of antiangiogenic agents with radiation therapy. The hypothesis is that the limitations of antiangiogenic agents and conventional modalities will be diminished when they are combined and a synergistic effect will result. The second specific aim is to develop and validate surrogates to monitor the effects of antiangiogenic therapy when given in combination with radiation therapy. Useful surrogates that predict for early tumor response are of critical importance for the incorporation of antiangiogenic therapy into clinical practice. The results obtained in these studies will have direct relevance to the planning of clinical trials for cancer.