Preclinical Models for Cancer Therapeutic Development

项目概要/摘要： 胰腺导管腺癌（PDA）是一种高度侵袭性和致死性疾病，部分原因是 与目前治疗方法的低效有关。因此，我的研究重点是识别 更好的PDAC治疗策略我们最近开发了一种离体胰腺导管 用于培养正常胰腺、早期胰腺癌和PDAC衍生的 三维基质胶基质内的组织。利用这些类器官，我们确定了基因 使用转录组学和蛋白质组学在正常和恶性细胞之间的表达改变 接近。这些基因对肿瘤生长或维持的作用将在功能上被证实。 使用原位移植类器官（OGO）小鼠移植模型验证。验证 然后将利用关键驱动因素来开发新的治疗策略。除了找到 新的候选药物靶点，我们进一步研究了转录因子Nrf2的作用， 我们发现，在胰腺肿瘤对PDAC进展的反应中， 传统的和新的治疗干预。我们最初的实验表明，Nrf2 作为抗氧化防御机制，氧化剂使PDAC细胞对翻译敏感 抑制，可作为治疗PDAC的新的治疗方法。我们 使用基因修饰小鼠模型（GEMM）进行临床前研究， 胰腺中的条件致癌Kras和突变的p53，以及小鼠和 人类OGO模型。GEMM和OGO模型开发了PDAC， 概括了人类疾病，并为模拟治疗干预提供了极好的平台。 我们将评估从两种基因表达变化中确定的药物组合的疗效 以及药物筛选方法。待测试的药物组合包括但不包括 不可逆ErbB途径抑制剂、AKT和MEK抑制剂、几种化合物 氧化剂和翻译抑制剂。这些努力将集中在化合物， 要么已经获得FDA批准，要么已经有了有希望的III期试验结果， 将我们的发现转化为临床。我在这些研究中的角色包括 用于全球分子分析的类器官库，以及改进识别候选人的工具 药物靶点此外，我将继续管理体内临床前研究，重点是 为胰腺癌寻找新的治疗方法最终，我的职责是确保 临床前研究的效率、再现性和准确性，从而促进有效的 将我们的发现转化为临床试验。

Project Summary/Abstract: Pancreatic Ductal Adenocarcinoma (PDA) is a highly aggressive and lethal disease in part due to the poor efficacy of current therapies. Therefore, my research focuses on the identification of better therapeutic strategies for PDAC. We recently developed an ex vivo, pancreatic ductal organoid system to culture normal pancreas, early-stage pancreatic cancer and PDAC-derived tissue inside a three dimensional, Matrigel matrix. Using these organoids, we identified gene expression alterations between normal and malignant cells using transcriptomic and proteomic approaches. The effect of these genes on tumor growth or maintenance will be functionally validated using orthotopically grafted organoid (OGO) mouse transplantation models. Validated key drivers will then be exploited to develop new therapeutic strategies. In addition to finding novel candidate drug targets, we have further investigated the role of Nrf2, a transcription factor we found to be important for PDAC progression, in the response of pancreatic tumors to traditional and novel therapeutic interventions. Our initial experiments suggest that Nrf2 serves as an anti-oxidant defense mechanism and that oxidants sensitize PDAC cells to translation inhibition, which can be used as a new therapeutic approach for the treatment of PDAC. We perform pre-clinical studies using genetically modified mouse models (GEMM) that express conditional oncogenic Kras and mutated p53 in the pancreas, as well as both mouse and human OGO models. The GEMM and OGO models develop PDAC, which accurately recapitulates human disease and provides excellent platforms to model therapeutic intervention. We will assess the efficacy of drug combinations identified from both gene expression changes as well as from drug screening approaches. Drug combinations to be tested include, but are not limited to, irreversible ErbB pathway inhibitors, inhibitors of AKT and MEK, several compounds with oxidant properties, and translation inhibitors. These efforts will focus on compounds that either already have FDA approval or have promising phase III trial results to facilitate rapid translation of our findings to the clinic. My role in these studies includes generation of an organoid library for global molecular analyses, as well as improving tools to identify candidate drug targets. Furthermore, I will continue to manage the in vivo preclinical studies that focus on discovering new therapeutic options for pancreatic cancer. Ultimately, my role will be to ensure the efficiency, reproducibility and accuracy of preclinical studies thereby facilitating the efficient translation of our findings into clinical trials.