Research Project 2

项目2概要 经过学术界和工业界几十年的密集努力，使用KRAS特定的 抑制剂（KRASi），如sotorasib和adagrasib，终于成为临床现实。但临床 对KRASi的反应在不同的癌症类型中差异很大（肺癌中较高，但结肠癌和直肠癌中较低）。 胰腺癌）并且通常不持久。重要的是，最终对KRASi产生耐药性的癌症 被发现已经获得了恢复KRAS信号传导的二级突变。对于这些患者， 强烈需要可以消除KRAS信号传导途径如RAF-MEK-KRAS的治疗组合。 ERK（MAPK）或PI 3 K-AKT级联。为了满足这些临床需求，WU-PDTC的项目2旨在测试 三种新的治疗组合，以加深KRASi在不同KRAS突变体中的治疗反应 癌症PDX因为这些组合策略是从胰腺癌模型中发展而来的，我们将 还进行最先进的蛋白质转录组学分析，以确定共同的和不同的主要和 胰腺癌、肺癌和结肠癌PDXs对KRAS和MAPK途径的继发性耐药机制a 两个人。我们的项目利用了来自不同癌症的基因定义的PDX模型的大量库， 类型，是基于新的令人兴奋的生物学，由国家的最先进的技术，包括创新的3D， 异型培养模型、空间-转录组学、snRNAseq、多重免疫组织化学和 优秀的生物信息学团队我们有强大的机构承担提供额外资金，以确保 本项目顺利实施。我们的新型治疗概念是基于治疗剂， 已经在临床试验中。如果成功，我们项目的结果可以立即转化为生物标志物- NCI实验治疗药物临床试验网络下驱动的临床试验，WU是该网络的活跃成员 参与成员。

PROJECT 2 SUMMARY After several decades of intensive efforts from academia and industry, targeting KRAS using KRAS-specific inhibitors (KRASi) such as sotorasib and adagrasib has finally become a clinical reality. However, clinical reponses to KRASi vary widely across different cancer types (higher in lung cancer, but much lower in colon and panceraic cancers) and are typically not durable. Importantly, cancers that eventually became resistant to KRASi were found to have acquired secondary mutations that restore KRAS signaling. For these patients, there is still a strong need for therapeutic combinations that can abrogate KRAS signaling pathways such as the RAF-MEK- ERK (MAPK) or PI3K-AKT cascades. To meet these clinical needs, Project 2 of the WU-PDTC aims at testing three novel therapeutic combinations to deepen the therapeutic response of KRASi in different KRAS-mutant cancer PDXs. Because these combinatorial strategies were developed from panceratic cancer models, we will also preform start-of-the-art proteo-transcriptomic analyses to determine the shared and distinct primary and secondary resistance mechanisms of pancreatic, lung and colon cancer PDXs to KRAS and MAPK pathwya inhibtiors. Our project capitalizes on the large repertoire of genetically-defined PDX models from different cancer types, is based on novel exciting biology, supported by state-of-the-art technqiues including innovative 3D- heterotypic culture model, spatio-transcriptomics, snRNAseq, multiplex immunohistochemistry and an outstanding bioinformatic team. We have strong institutional commitment to provide additional fund to ensure this Project is smoothly executed. Our novel therapeutic concepts are based on therapeutic agents that are already in clincial trials. If successful, results from our Project can be immediately translated into biomarker- driven clinical trials under the NCI Experimental Therapeutics Clinical Trials Network, in which WU is an active participating member.