Oncopigs as a better model for human cancer

描述（由申请人提供）：本项目由以下假设驱动：目前用于评估癌症治疗的体内模型对人体状况的预测性太差，无法有效使用。这可能成为将新的潜在药物转化为有效治疗方法的主要障碍。该项目旨在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。虽然猪已被广泛用于生物医学研究，但迄今为止，还没有报道转基因猪的癌症模型。像人类一样，猪可以活几十年，自发性癌症的发生率非常低。这与常见的啮齿动物癌症模型形成对比，后者的寿命仅限于几年，癌症的自发发展相当高。我们现在知道，需要5-6到6个遗传缺陷才能将正常的猪细胞转化为肿瘤细胞。这与人类相同。然而，小鼠细胞可以通过两次遗传损伤转化为肿瘤细胞。这些简单而深刻的遗传观察表明，猪是人类条件的一个更优越的上级模型系统。 我们建议使用最先进的技术，以产生转基因猪，可以被诱导失去三个主要的肿瘤抑制基因的表达，同时在乳房。这些改变将与生长激素受体的上调相结合。这些遗传缺陷通常在乳腺癌中发现，特别是在三阴性（TN）乳腺癌中。TN乳腺癌是一种特别侵袭性和难以治疗的乳腺癌形式，发病率高。我们将在系统中包括远红荧光蛋白，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具有丰富经验的实验室和在转基因猪的生产和饲养方面享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，以及任何此类癌症是否具有TN乳腺癌的特征。我们还将使用该群体来测试癌症化学预防剂的有效性，以及猪是否以与人类相似的方式对TN乳腺癌的一线治疗作出反应。 公共卫生相关性：该项目将建立一个新的模型系统，用于评估癌症的新治疗方法。该系统应该对人类状况更具预测性，从而增强识别和表征有效新型疗法的能力。它还可能为研究目前无法实际建模的癌症预防策略建立一个独特的模型。该模型针对乳腺癌，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.