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

基本信息

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
项目类别：
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

项目摘要

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/摘要：KRAS突变是癌症中最常见的畸变之一。突变克拉斯通过规范的RAS-RAF-MEK-ERK-RSK（RAS-RSK）信号传导驱动扩散和生存。尽管 Krasg12d，在癌症中发现的一个重大突变仍然不可用，较少的患者携带Krasg12c 新靶向药物出现的突变。已经研究了几种KRASG12C抑制剂临床和I/II/III期研究以及一项此类抑制剂Sotorasib已获得FDA批准KRASG12C突变体 NSCLC患者。尽管取得了成功，但Sotorasib或其他相关抑制剂的客观响应率具有谦虚，响应的持久性需要提高。许多电阻机制已经提出的和克服对KRASG12C抑制剂抗药性的策略是一个强烈的话题调查。我们发现RAS中的蛋白质会影响核蛋白的转运。正常细胞，核货物的导出是由核蛋白蛋白蛋白蛋白Exportin-1/XPO1通过核输出信号序列识别，并由RAS下游效应子rangtp促进。这使生长信号传导和核细胞质转运之间的介体可以通过古典RAS-RSK途径。 RAN结合蛋白3（RANBP3）被认为是通过RSK磷酸化的导致RANGDP通过RCC1促进RANGTP转换，从而增强RAN依赖性核质运输（架构）。这种过度活跃的核出口已显示可促进治疗通过错误定位抑制蛋白的失活而抗性。更重要的是，我们的新发现表明，核出口（SINE）化合物的特定抑制剂可以增强 KRASG12C抑制剂。我们假设正弦krasg12c抑制剂可能成为独特的组合 KRASG12C突变肿瘤。此外，研究这种独特的组合也将有助于发现切实的链接 KRAS和核蛋白出口信号传导之间。我们的具体目的是目标1。表征协同作用使用高吞吐量策略在正弦化合物和KRASG12CI之间。目标2。证明协同作用使用患者衍生的异种移植物在正弦krasg12ci之间。影响：突变的Kras仍然是无法穿透的要塞和未满足的临床需求。这项工作将导致一个针对的新颖组合的发展两个高度追捧的癌症靶标，即Krasg12c和XPO1。此外，提议的实验也将增强对突变体KRAS与核蛋白出口之间相互作用的基本理解途径及其耐药性的后果。拟议的临床前研究将提出一个新的和KRASG12C突变驱动抗性肿瘤的个性化疗法。