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在临床前肿瘤研究中显示出高度有效的策略，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却不太乐观。对这种差异的一种可能解释是，大多数人类癌症的血管系统对抗血管治疗的敏感性远低于临床前研究中使用的移植小鼠肿瘤模型。对周细胞的研究支持了这一观点，周细胞是覆盖微血管的间充质细胞，是其成熟过程的一部分。周细胞覆盖保护并标记出抗血管治疗的血管，在许多常见的人类癌症中，周细胞覆盖的血管比例明显高于移植的小鼠肿瘤。然而，某些原生小鼠乳腺癌，如在MMTV- new转基因小鼠和感染MMTV的小鼠中发生的乳腺癌，与人类癌症相似，其血管系统具有广泛的周细胞覆盖。重要的是，这些人也不太容易受到抗血管药物的影响。基于此，我们假设在MMTV-neu和MMTV-int-1转基因小鼠中发生的肿瘤比移植小鼠肿瘤更真实地模拟了人类常见癌症对抗血管药物的治疗反应。Aim 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类肿瘤中的血管和血管生成活性，验证MMTV-neu和MMTV-int-1肿瘤作为人类肿瘤血管系统的模型。Aim 2的研究包括MMTVneu和MMTV-int-1转基因小鼠的临床前试验，使用抗血管药物治疗已经形成的肿瘤，防止肿瘤形成，并与其他疗法联合使用。Aim 3的研究将通过基因治疗和转基因方法来降低MMTV-neu和MMTV-int-1肿瘤血管的周细胞覆盖，测试对Tie 2活性的操纵来改变肿瘤血管周细胞覆盖和对抗血管治疗的反应。总之，这些研究将证明MMTV-neu和MMTV-int-1转基因小鼠的乳腺肿瘤是否是人类肿瘤血管系统的优越模型，这些模型应该用于抗血管药物和策略的临床前评估，使其更有信息和预测患者的预后。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.