Feasibility and utility of MRI and dynamic 18F-FDG-PET in an orthotopic organoid-based patient-derived mouse model of endometrial cancer

Heidi Espedal,Kristine E Fasmer,Ingfrid S Haldorsen,Tina Fonnes,Camilla Krakstad,Hege F Berg

doi:10.1186/s12967-021-03086-9

Abstract

BackgroundPelvic magnetic resonance imaging (MRI) and whole-body positron emission tomography-computed tomography (PET-CT) play an important role at primary diagnostic work-up and in detecting recurrent disease in endometrial cancer (EC) patients, however the preclinical use of these imaging methods is currently limited. We demonstrate the feasibility and utility of MRI and dynamic 18F-fluorodeoxyglucose (FDG)-PET imaging for monitoring tumor progression and assessing chemotherapy response in an orthotopic organoid-based patient-derived xenograft (O-PDX) mouse model of EC.Methods18 O-PDX mice (grade 3 endometrioid EC, stage IIIC1), selectively underwent weekly T2-weighted MRI (total scans = 32), diffusion-weighted MRI (DWI) (total scans = 9) and dynamic 18F-FDG-PET (total scans = 26) during tumor progression. MRI tumor volumes (vMRI), tumor apparent diffusion coefficient values (ADCmean) and metabolic tumor parameters from 18F-FDG-PET including maximum and mean standard uptake values (SUVmax/SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic rate of 18F-FDG (MRFDG) were calculated. Further, nine mice were included in a chemotherapy treatment study (treatment; n = 5, controls; n = 4) and tumor ADCmean-values were compared to changes in vMRI and cellular density from histology at endpoint. A Mann–Whitney test was used to evaluate differences between groups.ResultsTumors with large tumor volumes (vMRI) had higher metabolic activity (MTV and TLG) in a clear linear relationship (r2 = 0.92 and 0.89, respectively). Non-invasive calculation of MRFDG from dynamic 18F-FDG-PET (mean MRFDG = 0.39 μmol/min) was feasible using an image-derived input function. Treated mice had higher tumor ADCmean (p = 0.03), lower vMRI (p = 0.03) and tumor cellular density (p = 0.02) than non-treated mice, all indicating treatment response.ConclusionPreclinical imaging mirroring clinical imaging methods in EC is highly feasible for monitoring tumor progression and treatment response in the present orthotopic organoid mouse model.

Highlights

Pelvic magnetic resonance imaging (MRI) and whole-body positron emission tomography-computed tomography (PET-CT) play an important role at primary diagnostic work-up and in detecting recurrent disease in endometrial cancer (EC) patients, the preclinical use of these imaging methods is currently limited
Imaging characteristics of the tumor in the mouse model versus the donor patient Preoperative pelvic MRI (Fig. 1A–C) and 18F-FDGPET-CT (Fig. 1D and E) in the donor woman with grade 3, endometrioid EC, Federation of Gynecology and Obstetrics (FIGO) stage IIIC1, exhibit tumor characteristics that are shared by the uterine tumor of the derived animal model (Fig. 1F–J)
In this study we demonstrate that advanced MRI and Positron emission tomography (PET) imaging methods in preclinical EC allow non-invasive and quantitative monitoring of tumor progression and treatment response

Summary

Introduction

Pelvic magnetic resonance imaging (MRI) and whole-body positron emission tomography-computed tomography (PET-CT) play an important role at primary diagnostic work-up and in detecting recurrent disease in endometrial cancer (EC) patients, the preclinical use of these imaging methods is currently limited. Successful translation of preclinical discoveries in oncology is rare [1] This may partly be due to lack of clinically relevant model systems and that preclinical imaging methods utilized for disease monitoring (e.g., optical imaging using fluorescence) are not feasible in the clinic [2]. We have recently developed EC organoid-based orthotopic mouse xenograft models (O-PDX) that recapitulate the histopathologic architecture, protein biomarker expression and the genetic profile of the donor tumor tissue [7]. These clinically relevant models respond well to conventional chemotherapeutic treatment and non-invasive imaging enables quantitative assessment of morphologicand metabolic tumor characteristics indicative of tumor progression or treatment response [7, 8]

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Conclusion