ABSTRACT
BACKGROUND: 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 (19F MRI) may allow noninvasive longitudinal imaging of immune cells. PURPOSE: Evaluating the potential of 19F MRI for monitoring changes in the tumor immune microenvironment, in response to combined SHP2/MEK inhibition. STUDY TYPE: Pre-clinical animal study. ANIMAL MODEL: 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 19F-perfluorocarbon (PFC) nanoparticles. ASSESSMENT: Upon tumor detection by conventional 1H MRI screening, 19F 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. 1H and 19F MRI was repeated 7 days and 14 days later. Pancreatic immune cell infiltrates were analyzed by flow cytometry and multiplex immunohistofluorescence (mIHF) upon sacrifice. STATISTICAL TESTS: Independent t-tests and one-way analysis of variance. RESULTS: 19F 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 19F MRI signal differences. DATA CONCLUSION: 19F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b+ macrophages/monocytes in pancreatic cancer. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
ABSTRACT
LIN28B is an RNA-binding protein that targets a broad range of microRNAs and modulates their maturation and activity. Under normal conditions, LIN28B is exclusively expressed in embryogenic stem cells, blocking differentiation and promoting proliferation. In addition, it can play a role in epithelial-to-mesenchymal transition by repressing the biogenesis of let-7 microRNAs. In malignancies, LIN28B is frequently overexpressed, which is associated with increased tumor aggressiveness and metastatic properties. In this review, we discuss the molecular mechanisms of LIN28B in promoting tumor progression and metastasis in solid tumor entities and its potential use as a clinical therapeutic target and biomarker.