Clinical Translation of Nuclear Export Inhibitor in Metastatic Pancreatic Cancer

核输出抑制剂在转移性胰腺癌中的临床转化

• 批准号: 10443040
• 负责人: Asfar S Azmi
• 金额: $ 34.49万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443040
• 关键词: Binding Proteins; Biological; CRISPR/Cas technology; Cell Nucleus; Cell model; Cells; Clinical; Combined Modality Therapy; Computational Biology; Correlative Study; Coupled; Critical Pathways; Data; Desmoplastic; Disease; Drug Targeting; Expression Profiling; FBXW7 gene; Fibroblasts; Genes; Global Change; Grant; Growth; Investigation; KPC model; KRAS2 gene; KRASG12D; Karyopherins; Knowledge; Link; MEKs; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; Methodology; Modeling; Mutation; Non-Small-Cell Lung Carcinoma; Normal Cell; Nuclear; Nuclear Export; Nuclear Protein; Oncogenic; Oral Administration; Organoids; Outcome; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Pathway Analysis; Pathway interactions; Patient Recruitments; Patients; Penetrance; Peptide Signal Sequences; Pharmaceutical Preparations; Phase; Phase Ib/II Clinical Trial; Phase Ib/II Trial; Phosphorylation; Process; Proliferating; Protein Export Pathway; Protein Family; Proteins; RAS driven tumor; RNA Interference; Ras/Raf; Recruitment Activity; Regimen; Reporting; Residual Neoplasm; Resistance; Role; Running; Safety; Signal Transduction; Specificity; Specimen; Transgenic Organisms; Tumor Suppressor Proteins; Vascularization; Work; analog; biomarker development; biomarker identification; clinical translation; epithelial to mesenchymal transition; experimental study; exportin 1 protein; gemcitabine; genome editing; improved; in vivo; inhibitor; innovation; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; nucleocytoplasmic transport; objective response rate; overexpression; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; patient derived xenograft model; patient subsets; personalized medicine; pharmacodynamic biomarker; pre-clinical; preclinical study; protein transport; resistance mechanism; response; response biomarker; stemness; subcutaneous; success; synergism; targeted treatment; therapy design; therapy outcome; therapy resistant; transcriptome sequencing; treatment response; tumor

Abstract/Summary: Mutations in KRAS are among the most common aberrations in cancer. Mutant KRAS drives proliferation and survival through canonical RAS-RAF-MEK-ERK-RSK (RAS-RSK) signaling. While KRASG12D, a major mutation found in cancers remains undruggable, a smaller subset of patients carry KRASG12C mutation for which new targeted drugs have emerged. Several KRASG12C inhibitors have been studied in pre- clinical and Phase I/II/III studies and one such inhibitor sotorasib has received FDA approval for KRASG12C mutant NSCLC patients. Despite this success, the objective response rates from sotorasib or other related inhibitors has been modest and durability of response needs to be improved. A number of resistance mechanism have been proposed and strategies to overcome therapy resistance to KRASG12C inhibitors is a topic of intense investigations. We have discovered that proteins in the RAS can influence the nuclear protein transport. In normal cells, the export of nuclear cargoes is mediated by the Karyopherin family protein exportin-1/XPO1 through nuclear export signal sequence recognition and is facilitated by a RAS downstream effector RanGTP. This makes RAN a mediator between growth signaling and nucleocytoplasmic transport that can be activated through classical RAS-RSK pathway. Ran binding protein 3 (RanBP3) is recognized to be phosphorylated through RSK, resulting in the promotion of RanGDP to RanGTP conversion through RCC1 thereby enhancing Ran-dependent nucleocytoplasmic transport (schema). Such over-active nuclear export has been shown to promote therapy resistance through mislocalization dependent inactivation of tumor suppressor proteins. More significantly, our new findings show that specific inhibitors of nuclear export (SINE) compounds can enhance the efficacy of KRASG12C inhibitors. We hypothesize that SINE-KRASG12C inhibitors could become a unique combination for KRASG12C mutant tumors. Additionally, studying this unique combination will also help uncover the tangible link between KRAS and nuclear protein export signaling. Our specific aims are Aim 1. Characterize the synergy between SINE compounds and KRASG12Ci using high throughput strategies. Aim 2. Demonstrate synergy between SINE KRASG12Ci using patient derived xenograft. Impact: Mutant KRAS remains an impenetrable fortress and an unmet clinical need. This work will lead to the advancement of a novel combination that target two highly sought after cancer targets i.e. KRASG12C and XPO1. Additionally, the proposed experiments will also enhance the fundamental understanding of the interaction between mutant KRAS and nuclear protein export pathways and its consequence of therapy resistance. The proposed pre-clinical studies will bring forward a new and personalized therapy for KRASG12C mutant driven resistant tumors.

摘要/总结：KRAS 突变是癌症中最常见的畸变之一。突变型KRAS 通过规范的 RAS-RAF-MEK-ERK-RSK (RAS-RSK) 信号传导驱动增殖和存活。尽管 KRASG12D，一种在癌症中发现的主要突变，仍然无法用药物治疗，一小部分患者携带 KRASG12C 针对突变，新的靶向药物已经出现。几种 KRASG12C 抑制剂已在预研究中进行了研究。 临床和 I/II/III 期研究，其中一种抑制剂 sotorasib 已获得 FDA 批准用于 KRASG12C 突变体 非小细胞肺癌患者。尽管取得了这一成功，但 sotorasib 或其他相关抑制剂的客观反应率 反应的持久性需要提高。多种抵抗机制被提出 克服 KRASG12C 抑制剂治疗耐药性的建议和策略是一个激烈的话题 调查。我们发现 RAS 中的蛋白质可以影响核蛋白转运。正常情况下 在细胞中，核货物的输出是由核转运蛋白家族蛋白exportin-1/XPO1介导的 核输出信号序列识别，并由 RAS 下游效应器 RanGTP 促进。这 使 RAN 成为生长信号传导和核质运输之间的介质，可通过以下方式激活： 经典 RAS-RSK 途径。 Ran 结合蛋白 3 (RanBP3) 被认为通过 RSK 被磷酸化， 导致通过 RCC1 促进 RanGDP 向 RanGTP 的转化，从而增强 Ran 依赖性 核细胞质运输（模式）。这种过度活跃的核输出已被证明可以促进治疗 通过肿瘤抑制蛋白的错误定位依赖性失活来产生耐药性。更重要的是，我们的 新的研究结果表明，特定的核输出抑制剂（SINE）化合物可以增强 KRASG12C 抑制剂。我们假设 SINE-KRASG12C 抑制剂可能成为一种独特的组合 KRASG12C 突变肿瘤。此外，研究这种独特的组合也将有助于揭示有形的联系 KRAS 和核蛋白输出信号之间的关系。我们的具体目标是目标 1：表征协同作用 使用高通量策略在 SINE 化合物和 KRASG12Ci 之间进行比较。目标 2. 发挥协同作用 SINE KRASG12Ci 之间使用患者来源的异种移植物。影响：突变的 KRAS 仍然是一个坚不可摧的 堡垒和未满足的临床需求。这项工作将导致一种新颖的组合的进步，该组合的目标是 两个备受追捧的癌症靶标，即 KRASG12C 和 XPO1。此外，拟议的实验还将 增强对突变型 KRAS 与核蛋白输出之间相互作用的基本理解 途径及其治疗抵抗的后果。拟议的临床前研究将提出新的 针对 KRASG12C 突变驱动的耐药肿瘤的个性化治疗。