Reichardt Wilfried, Gewalt Tabea, Hafner Philipp, Keller Steffen J, Chen Xun, Alrawashdeh Asma, Li Yayu, Besson Solène, Fichtner-Feigl Stefan, von Elverfeldt Dominik, Jumaa Huda, Ruess Dietrich A
Division of Medical Physics, Department of Diagnostic and Interventional Radiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.
J Magn Reson Imaging. 2025 Apr;61(4):1996-2008. doi: 10.1002/jmri.29589. Epub 2024 Aug 27.
Pancreatic cancer has a poor prognosis. Targeting Kirsten Rat Sarcoma (KRAS) mutation and its related pathways may enhance immunotherapy efficacy. While in vivo monitoring of therapeutic response and immune cell migration remains challenging, Fluorine-19 MRI (F MRI) may allow noninvasive longitudinal imaging of immune cells.
Evaluating the potential of F MRI for monitoring changes in the tumor immune microenvironment, in response to combined SHP2/MEK inhibition.
Pre-clinical animal study.
Murine genetically engineered pancreatic cancer model (N = 20, both sexes).
FIELD STRENGTH/SEQUENCE: 9.4-T, two-dimensional multi-slice Rapid Acquisition with Relaxation Enhancement sequence. Intravenous injection of F-perfluorocarbon (PFC) nanoparticles.
Upon tumor detection by conventional H MRI screening, F MRI was performed in mice 24 hours after PFC nanoparticle administration. Animals were randomly assigned to four treatment groups: allosteric Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor SHP099, the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor Trametinib, the combination of both, or a vehicle control (4 to 6 mice each group), administered every other day per oral gavage. H and F MRI was repeated 7 days and 14 days later. Pancreatic immune cell infiltrates were analyzed by flow cytometry and multiplex immunohistofluorescence (mIHF) upon sacrifice.
Independent t-tests and one-way analysis of variance.
F MRI revealed continuous decrease of PFC-signals in tumors from vehicle controls (100%, 80%, and 74% on days 0, 7, and 14, respectively), contrasting with stable or increasing signals under KRAS-pathway-directed treatment. MEK inhibition showed 100%, 152%, and 84% and dual SHP2/MEK1/2 inhibition demonstrated signals of 100%, 134%, and 100% on days 0, 7, 14, respectively. mIHF analyses indicated CD11b macrophages/monocytes as primary contributors to the observed F MRI signal differences.
F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b macrophages/monocytes in pancreatic cancer.
1 TECHNICAL EFFICACY: Stage 2.
胰腺癌预后较差。靶向 Kirsten 大鼠肉瘤（KRAS）突变及其相关通路可能会提高免疫治疗效果。虽然对治疗反应和免疫细胞迁移进行体内监测仍然具有挑战性，但氟 - 19磁共振成像（F MRI）可能允许对免疫细胞进行无创纵向成像。
评估 F MRI 在监测肿瘤免疫微环境变化以应对 SHP2/MEK 联合抑制方面的潜力。
临床前动物研究。
小鼠基因工程胰腺癌模型（N = 20，雌雄均有）。
场强/序列：9.4 - T，二维多层快速采集弛豫增强序列。静脉注射 F - 全氟碳（PFC）纳米颗粒。
通过传统 H MRI 筛查检测到肿瘤后，在给予 PFC 纳米颗粒 24 小时后对小鼠进行 F MRI 检查。将动物随机分为四个治疗组：变构含Src同源2结构域蛋白酪氨酸磷酸酶2（SHP2）抑制剂 SHP099、丝裂原活化细胞外信号调节激酶1/2（MEK1/2）抑制剂曲美替尼、两者联合使用或载体对照（每组4至6只小鼠），每隔一天经口灌胃给药。7天和14天后重复进行 H 和 F MRI 检查。处死动物后通过流式细胞术和多重免疫组织荧光（mIHF）分析胰腺免疫细胞浸润情况。
独立 t 检验和单因素方差分析。
F MRI 显示载体对照组肿瘤中 PFC 信号持续下降（分别在第0、7和14天为100%、80%和74%），与 KRAS 通路导向治疗下信号稳定或增加形成对比。MEK 抑制在第0、7、14天分别显示信号为100%、152%和84%，双重 SHP2/MEK1/2 抑制分别显示信号为100%、134%和100%。mIHF 分析表明 CD11b 巨噬细胞/单核细胞是观察到的 F MRI 信号差异的主要贡献者。
F MRI 可能为胰腺癌中 CD11b 巨噬细胞/单核细胞的丰度和空间分布提供无创纵向估计。
1 技术疗效：2期。
