Research Project 2

研究项目2

• 批准号: 10732991
• 负责人: Kian H Lim
• 金额: $ 23.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732991
• 关键词: 3-Dimensional; Academia; Autophagocytosis; Benchmarking; Bioinformatics; Biological Markers; Biology; Blood; Cancer Model; Clinical; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Collaborations; Colon; Colon Carcinoma; Cytotoxic Chemotherapy; Data; Development; Disease Progression; ERBB2 gene; Ensure; Exposure to; Funding; Future; Genes; Genomics; Immunohistochemistry; In Vitro; Industry; Inflammatory; Institution; Investigational Therapies; KRAS2 gene; KRASG12D; Letters; Lung; MAPKAPK2 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Mus; Mutation; NF-kappa B; Oncogenes; Oncoproteins; Organ; PIK3CG gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphotransferases; Prediction of Response to Therapy; Proteomics; Proto-Oncogene Proteins c-akt; Research Project Grants; Resistance; Signal Pathway; Signal Transduction; Stress; Surface; TNF gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Topoisomerase-I Inhibitor; Translating; Trastuzumab; Universities; Washington; Work; Xenograft procedure; antibody conjugate; autocrine; biomarker driven; biomarker identification; cancer type; chemotherapy; combinatorial; efficacy evaluation; efficacy testing; improved; in vivo; inhibitor; innovation; malignant breast neoplasm; member; multiple omics; mutant; novel; novel strategies; novel therapeutics; objective response rate; pancreatic ductal adenocarcinoma cell; patient derived xenograft model; pharmacologic; pre-clinical; preclinical efficacy; predictive marker; protein kinase inhibitor; receptor; resistance mechanism; response; success; systemic toxicity; transcriptomics; treatment response; tumor; tumor growth

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.

项目2总结 经过学术界和工业界几十年的密集努力，使用特定于KRAS的KRAS 抑制剂(Krasi)，如sotorasib和adagrasib终于成为临床现实。然而，临床上 对Krasi的反应在不同的癌症类型中差别很大(肺癌的反应较高，但在结肠癌和 泛癌)，通常不会持久。重要的是，最终对克拉西产生抗药性的癌症 发现获得了恢复KRAS信号的次级突变。对于这些患者来说，仍然有 迫切需要能够废除KRAS信号通路的治疗组合，如RAF-MEK- ERK(MAPK)或PI3K-AKT级联。为了满足这些临床需求，WU-PDTC的项目2旨在测试 三种新的治疗组合加深Krasi对不同KRAS突变的治疗反应 癌症PDX。因为这些组合策略是从胰腺癌模型发展而来的，我们将 还可以进行最先进的蛋白质转录分析，以确定共有的和不同的初级和 胰腺癌、肺癌和结肠癌PDX对KRAS和MAPK通路的继发性耐药机制 抑制剂。我们的项目利用了来自不同癌症的大量基因定义的PDX模型 类型，是基于新的令人兴奋的生物学，由包括创新的3D- 异型培养模型、空间转录组学、SNRNAseq、多重免疫组织化学和AN 杰出的生物信息学团队。我们有坚定的机构承诺提供额外资金，以确保 本项目顺利实施。我们的新治疗概念基于治疗剂， 已经在进行临床试验。如果成功，我们项目的结果可以立即转化为生物标志物- 在NCI实验治疗临床试验网络下的驱动临床试验，其中吴是活跃的 参与成员。