Transgenic Mice as Models for Antivascular Therapy

描述（由申请人提供）：通过靶向血管治疗癌症是一种基于其合理的科学原理并且已被证明在临床前肿瘤研究中非常有效的策略，因此引起了极大的热情。然而，这种疗法的人体临床试验结果不太有希望。这种差异的一个潜在解释是，大多数人类癌症中的血管系统比临床前研究中使用的移植小鼠肿瘤模型中的血管系统对抗血管治疗的敏感性低得多。支持这一点的是对周细胞的研究，周细胞是间充质细胞，作为其成熟过程的一部分覆盖微血管。周细胞覆盖保护和标记抗血管治疗的血管，并且周细胞覆盖的血管的分数在许多常见的人类癌症中显著高于移植的小鼠肿瘤。然而，某些自体小鼠乳腺癌，如MMTV-neu转基因小鼠和感染MMTV的小鼠中出现的那些，在具有广泛周细胞覆盖的脉管系统方面类似于人类癌症。重要的是，这些也可能不太容易受到抗血管药物的影响。基于此，假设MMTV-neu和MMTV-int-1转基因小鼠中产生的癌症比移植的小鼠肿瘤更忠实地模拟常见人类癌症对抗血管药物的治疗反应。目标1中提出的研究将通过使用各种组织病理学技术比较小鼠和人肿瘤中的血管和血管生成活性来验证MMTV-neu和MMTV-int-1肿瘤作为人肿瘤血管系统模型。目标2中的研究包括在MMTVneu和MMTV-int-1转基因小鼠中进行的临床前试验，使用抗血管药物治疗已形成的肿瘤，预防肿瘤形成并与其他疗法联合使用。目标3中的研究将测试Tie 2活性的操作以改变肿瘤血管周细胞覆盖率和对抗血管治疗的反应，使用基因治疗和转基因方法来减少MMTV-neu和MMTV-int-1肿瘤血管的周细胞覆盖率。总之，这些研究将证明MMTV-neu和MMTV-int-1转基因小鼠中的乳腺肿瘤是否是人类肿瘤血管系统的上级模型，其应用于抗血管药物和策略的临床前评价，以使其更能提供信息并预测患者的结局。这些模型的使用将促进抗血管药物的开发，并使其更有效地过渡到临床。

DESCRIPTION (provided by applicant): Treating cancers by targeting their blood vessels is a strategy that has generated great enthusiasm based on its sound scientific rationale and because it has been shown to be highly effective in preclinical tumor studies. However, the results of human clinical trials of this therapy have been less promising. A potential explanation for this disparity is that the vasculature in most human cancers is much less susceptible to antivascular therapy than those in the transplanted mouse tumor models used in preclinical studies. Support for this comes from study of pericytes, which are mesenchymal cells that cover microvessels as part of their maturation process. Pericyte coverage protects and marks vessels that are resistant to antivascular therapy, and the fraction of pericyte-covered vessels is significantly higher in many common human cancers than in transplanted mouse tumors. However, certain autochthonous mouse mammary carcinomas, like those arising in MMTV-neu transgenic mice and mice infected with MMTV, resemble human cancers in having vasculature with extensive pericyte coverage. Importantly, these may also be less susceptible to antivascular agents. Based on this, carcinomas arising in MMTV-neu and MMTV-int-1 transgenic mice are hypothesized to more faithfully model the therapeutic response of common human cancers to antivascular agents than transplanted mouse tumors. Studies proposed in Aim 1 will validate MMTV-neu and MMTV-int-1 tumors as models of human tumor vasculature by comparing vessels and angiogenic activity in mouse and human tumors using a variety of histopathologic techniques. Studies in Aim 2 consist of preclinical trials in MMTVneu and MMTV-int-1 transgenic mice using antivascular agents to treat tumors that have formed, to prevent tumors from forming and in combination with other therapies. Studies in Aim 3 will test manipulation of Tie 2 activity to alter tumor vessel pericyte coverage and response to antivascular therapy using both gene therapy and transgenic approaches to reduce pericyte coverage of MMTV-neu and MMTV-int-1 tumor vessels. Together, these studies will demonstrate whether mammary tumors in MMTV-neu and MMTV-int-1 transgenic mice are superior models of human tumor vasculature which should be used in preclinical evaluation of antivascular agents and strategies to make it more informative and predictive of outcome in patients. Use of such models will enhance development of antivascular agents and make their transition into the clinic more efficient and effective.