Identification of Potential MR-Derived Biomarkers for Tumor Tissue Response to 177Lu-Octreotate Therapy in an Animal Model of Small Intestine Neuroendocrine Tumor

Abstract

Magnetic resonance (MR) methods enable noninvasive, regional tumor therapy response assessment, but associations between MR parameters, underlying biology, and therapeutic effects must be investigated. The aim of this study was to investigate response assessment efficacy and biological associations of MR parameters in a neuroendocrine tumor (NET) model subjected to radionuclide treatment. Twenty-one mice with NETs received 177Lu-octreotate at day 0. MR experiments (day −1, 1, 3, 8, and 13) included T2-weighted, dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) and relaxation measurements (T1/T2*). Tumor tissue was analyzed using proteomics. MR-derived parameters were evaluated for each examination day and for different radial distances from the tumor center. Response assessment efficacy and biological associations were evaluated using feature selection and protein expression correlations, respectively. Reduced tumor growth rate or shrinkage was observed until day 8, followed by reestablished growth in most tumors. The most important MR parameter for response prediction was DCE-MRI–derived pretreatment signal enhancement ratio (SER) at 40% to 60% radial distance, where it correlated significantly also with centrally sampled protein CCD89 (association: DNA damage and repair, proliferation, cell cycle arrest). The second most important was changed diffusion (D) between day −1 and day 3, at 60% to 80% radial distance, where it correlated significantly also with peripherally sampled protein CATA (association: oxidative stress, proliferation, cell cycle arrest, apoptotic cell death). Important information regarding tumor biology in response to radionuclide therapy is reflected in several MR parameters, SER and D in particular. The spatial and temporal information provided by MR methods increases the sensitivity for tumor therapy response.

Multiparametric MR for non‐invasive evaluation of tumour tissue histological characteristics after radionuclide therapy

“…Dalmo et al ., 2017). The initial 21 animals were included in our mpMR project, including studies on the longitudinal behaviour of MR‐derived tissue parameters in response to therapy and optimization of image post processing techniques, both with different specific aims and results. Based on inclusion criteria described below, n = 5 of the 21 animals were evaluated in the current study.…”

“…Several functional MR imaging methods are currently being investigated for their ability to indirectly measure tumour characteristics. Promising results regarding early assessment of tumour response to RNT have been found . For example, dynamic contrast‐enhanced MR imaging (DCE‐MRI) is used in oncological imaging to reveal abnormal biokinetic interactions between tumour tissue and contrast material.…”

“…Promising results regarding early assessment of tumour response to RNT have been found. 1,4 For example, dynamic contrast-enhanced MR imaging (DCE-MRI)…”

Data‐driven identification of tumor subregions based on intravoxel incoherent motion reveals association with proliferative activity

“…The study was approved by the Ethical Committee on Animal Research in Gothenburg, Sweden. Data from the animals were also included in a previous study on therapy response assessment …”

“…Several methods have been suggested for identification of tumor subregions based on MRI . The methods have been based on geometrical parameters, such as radial distance from the tumor center, as well as functional characteristics based on different quantitative imaging‐derived parameters, either by predefined thresholds or by partitioning derived from the data itself . Among the data‐driven approaches, clustering methods such as k‐means clustering or Gaussian mixture models (GMM) have been proposed to enable partitioning of tumor voxels based on multiparametric data .…”