Oncopigs as a better model for human cancer

描述(由申请人提供)：该项目是由一种假设驱动的，即目前用于评估癌症治疗的体内模型对于有效使用人类状况过于不可预测。这可能成为将新的潜在药物转化为患者有效疗法的主要障碍。该项目建议确定转基因猪是否可以作为一种新的、更像人类的癌症模型。尽管猪在生物医学研究中得到了广泛的应用，但到目前为止，还没有转基因猪癌症模型的报道。像人类一样，猪可以活几十年，而且自发性癌症的发生率非常低。这与常见的以啮齿动物为基础的癌症模型形成了鲜明对比，在这种模型中，寿命被限制在几年内，癌症的自发发展相当高。我们现在知道，将一个正常的猪细胞转化为肿瘤细胞需要5-6到6个基因缺陷。这与人类的情况相同。然而，小鼠细胞只需两次遗传损伤就可以转化为肿瘤细胞。这些简单而深刻的遗传学观察表明，猪是人类状况的一个优越的模型系统。我们建议使用最先进的技术来产生转基因猪，这些转基因猪可以被诱导同时失去乳房中三个主要肿瘤抑制基因的表达。这些变化将伴随着生长激素受体的上调。这些基因缺陷常见于乳腺癌，尤其是三阴性(TN)乳腺癌。TN乳腺癌是一种侵袭性特别强、治疗难度大、发病率高的乳腺癌。我们将在该系统中包括一种远红色荧光蛋白，这将允许对诱导的乳腺细胞的状态进行非侵入性成像。该项目将涉及在人类乳腺癌的分子和细胞生物学方面拥有丰富经验的实验室以及在转基因猪的生产和饲养方面具有世界声誉的实验室之间的合作。将对动物进行测试，以确定这些病变是否足以引发乳腺癌，以及是否有任何此类癌症具有TN乳腺癌的特征。我们还将利用人群来测试癌症化学预防药物的有效性，以及猪对TN乳腺癌一线治疗的反应是否与人类相似。 公共卫生相关性：该项目将建立一个新的模型系统来评估癌症的新治疗方法。该系统应该更好地预测人类的状况，从而增强识别和表征有效的新疗法的能力。它还可能为癌症预防策略的研究建立一个独特的模型，目前还无法现实地建模。该模型是针对乳腺癌的，因为由于缺乏足够有效的治疗方法，预计美国每年有超过4万名妇女死于这种疾病。

DESCRIPTION (provided by applicant): This project is driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research, to date, there is no reported transgenic swine model for cancer. Like humans, pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models, where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However, mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition. We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells. The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs. Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents, and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans. PUBLIC HEALTH RELEVANCE: This project will establish a novel model system for evaluating new therapeutic approaches to cancer. The system should be much more predictive for the human condition, thus enhancing the ability to identify and characterize effective novel therapeutics. It may also establish a unique model for the study of cancer preventative strategies that cannot be realistically modeled at present. The model is targeted towards breast cancer as over 40 thousand women are expected to die in the United states each year from this disease due to lack of sufficiently effective therapies.