Preclinical Models for Cancer Therapeutic Development

项目摘要/摘要： 胰腺导管腺癌(PDA)是一种高度侵袭性和致命性的疾病，部分原因是 目前的治疗方法疗效不佳。因此，我的研究重点放在鉴定上 更好的治疗PDAC的策略。我们最近开发了一种体外胰腺导管 器官系统培养正常胰腺、早期胰腺癌及PDAC来源的研究 一个三维的Matrigel矩阵中的组织。利用这些有机化合物，我们鉴定了基因 用转录和蛋白质组学方法研究正常细胞和肿瘤细胞的表达变化 接近了。这些基因对肿瘤生长或维持的影响将是功能上的 使用原位移植器官(OGO)小鼠移植模型进行验证。经过验证 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， 传统的和新型的治疗干预。我们的初步实验表明，NRF2服务于 作为一种抗氧化防御机制，以及氧化剂使PDAC细胞对翻译敏感 抑制可作为治疗PDAC的一种新方法。我们 使用转基因小鼠模型(GEMM)进行临床前研究， 胰腺中条件性致癌基因Kras和突变的P53，以及小鼠和 真人奥戈模特。GEMM和OGO模型开发了PDAC，该模型能够准确地 概述了人类疾病，并提供了极好的平台来模拟治疗干预。 我们将评估根据这两种基因表达变化确定的药物组合的有效性。 以及药物筛选方法。需要测试的药物组合包括，但不是 仅限于不可逆的ErbB途径抑制剂，AKT和MEK的抑制剂，几种化合物 具有氧化剂特性和翻译抑制剂。这些努力将集中在以下化合物上 要么已经获得FDA批准，要么有前景看好的III期试验结果，以促进快速 将我们的发现翻译到临床上。我在这些研究中的角色包括生成一个 用于全球分子分析的有机类库，以及用于识别候选对象的改进工具 毒品目标。此外，我将继续管理体内的临床前研究，重点是 发现胰腺癌的新治疗方案。归根结底，我的角色是确保 临床前研究的效率、重复性和准确性，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.