Transgenic Mice as Models for Antivascular Therapy

描述(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理论和在临床前肿瘤研究中被证明是高度有效的策略，已经引起了极大的热情。然而，这种疗法的人体临床试验结果并不那么令人乐观。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鼠肿瘤模型中的血管系统更不容易受到抗血管治疗的影响。支持这一点的是对周细胞的研究，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。周细胞覆盖保护和标记抵抗抗血管治疗的血管，在许多常见的人类癌症中，周细胞覆盖的血管的比例明显高于移植的小鼠肿瘤。然而，某些固有的小鼠乳腺癌，如发生在MMTV-neu转基因小鼠和感染MMTV的小鼠中的乳腺癌，在具有广泛周细胞覆盖的血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，在MMTV-neu和MMTV-int-1转基因小鼠中产生的癌症被假设为比移植的小鼠肿瘤更真实地模拟常见人类癌症对抗血管药物的治疗反应。在Aim 1上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动来验证MMTV-neu和MMTV-int-1肿瘤作为人类肿瘤血管模型的有效性。Aim 2的研究包括在MMTVneu和MMTV-int-1转基因小鼠上进行的临床前试验，使用抗血管药物治疗已经形成的肿瘤，防止肿瘤形成，并与其他治疗方法相结合。目标3中的研究将测试Tie 2活性的操纵，以改变肿瘤血管周细胞覆盖率，并使用基因疗法和转基因方法来减少MMTV-neu和MMTV-int-1肿瘤血管周细胞覆盖率，以及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的更好模型，应该用于抗血管药物的临床前评估，以及使其更具信息性和对患者结果的预测的策略。这些模型的使用将促进抗血管药物的发展，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.