1 of 3 Interdisciplinary Collaboratory for Enhancing Translational Therapeutics Utilizing Biologically, Immunologically, and Metabollically Relevant Models of Breast Cancer

 描述（由申请人提供）：目前癌症治疗的临床前试验通常包括小动物（通常为小鼠）研究，然后是灵长类动物研究，以在进入I期试验之前快速评估总体毒性。使事情进一步复杂化的是，临床前研究通常是在年轻的、瘦的、近交的、无特定病原体（SPF）的生物体上进行的，这不能准确地反映典型癌症患者的人口统计学特征。为了解决这些差异，我们的研究中心特别建议利用加州大学戴维斯分校的独特环境，该环境将使用来自加州大学戴维斯分校兽医学院的小鼠模型和大型动物模型（即犬）进行联合收割机基础研究。除了多物种比较之外，我们还特别适合解决年龄和BMI相关的反应，这些反应尚未在任何一个模型中广泛确定，但仅在多个物种中得到证实。我们将广泛表征和整合基于各种检测的反应，并寻找共性作为结果的可预测标志物，重点关注年龄和BMI的差异，以证明临床前模型需要反映癌症患者的表型。最后，我们将使用来自小鼠和犬肿瘤模型的样本验证我们的研究结果，这又是加州大学戴维斯分校特有的另一个独特属性，它可以通过兽医教学医院接触犬癌症患者。 总的来说，我们的赠款提案与我们的合作提案有关，该提案旨在将三个专业实验室联系起来， 一项多学科合作研究，旨在提高小鼠癌症和肿瘤模型在转化研究中的实用性。每个相关的提案将整合成像科学、免疫学和病理生物学，以推进当前的标准实践，即使用瘦的、年轻的、SPF模型和细胞培养衍生的肿瘤进入人口统计学上合适的小鼠模型，共同关注人类癌前病变的乳腺上皮内瘤样生长（MINO）模型的利用（由卡迪夫博士的实验室提供）。我们的研究结果将共同解决目前临床前和临床结果之间的不一致，并通过定义更合适的模型来证明克服这些限制的方法，这些模型将增加临床的可移植性。

 DESCRIPTION (provided by applicant): Current preclinical testing for cancer therapeutics generally consists of small animal (typically murine) studies followed by studies in primates to quickly assess gross toxicities prior to moving into phase I trials. To further complicate things, preclinical studies are often performed on young, lean, inbred, specific pathogen free (SPF) organisms which do not accurately reflect the demographic of the typical cancer patient. To address these discrepancies, our site is specifically proposing to utilize the unique environment at UC Davis which will combine basic research using murine models and large animal models, namely canines, from the UC Davis School of Veterinary Medicine. In addition to the multi-species comparisons, we are uniquely suited to address age and BMI related responses, which have not been extensively determined in any one model, yet alone confirmed across multiple species. We will extensively characterize and integrate responses based on a variety of assays and look for commonalities as predictable markers of outcomes focusing on differences with age and BMI to demonstrate that preclinical models need to be reflective of the cancer patient phenotype. Finally, we will be validating our findings using samples from both murine and canine tumor models, again another unique attribute specific to UC Davis which has access to canine cancer patients through the Veterinary Medical Teaching Hospital. Overall, our grant proposal ties into our collaborative proposal, which aims to link three specialized laboratories in a multi-disciplinary collaborative study to improve the utility of mouse cancer and tumor models for translational research. Each linked proposal will integrate imaging sciences, immunology, and pathobiology to advance current standard practices of using lean, young, SPF models and cell-culture-derived tumors into demographically appropriate mouse models with a shared focus on utilization of the mammary intraepithelial neoplasia outgrowth (MINO) model of human pre-cancer (provided by Dr. Cardiff's laboratory). The findings from our studies will together address the current incongruence between preclinical and clinical outcomes, and also demonstrate means to overcome these limitations through defining more appropriate models that will increase translatability into the clinic.