Multimodal Imaging with ¹⁸F-FDG PET and Cerenkov Luminescence Imaging After MLN4924 Treatment in a Human Lymphoma Xenograft Model

Abstract

Cerenkov luminescence imaging (CLI) is an emerging imaging technique that combines aspects of both optical and nuclear imaging fields. The ability to fully evaluate the correlation and sensitivity of CLI to PET is critical to progress this technique further for use in high-throughput screening of pharmaceutical compounds. To achieve this milestone, it must first be established that CLI data correlate to PET data in an in vivo preclinical antitumor study. We used MLN4924, a phase 2 oncology therapeutic, which targets and inhibits the NEDD8-activating enzyme pathway involved in the ubiquitin-proteasome system. We compared the efficacious effects of MLN4924 using PET and Cerenkov luminescence image values in the same animals. Methods: Imaging of 18 F-FDG uptake was performed at 5 time points after drug treatment in the subcutaneously implanted diffuse large B-cell lymphoma tumor line OCI-Ly10. Data were acquired with both modalities on the same day, with a 15-min delay between CLI and PET. PET data analysis was performed using percentage injected dose per cubic centimeter of tissue (%ID/cm 3 ), average standardized uptake values, and total glycolytic volume. CLI measurements were radiance, radiance per injected dose (radiance/ID), and total radiant volume. Results: A strong correlation was found between PET total glycolytic volume and CLI total radiant volume (r 2 5 0.99) and various PET and CLI analysis methods, with strong correlations found between PET %ID/cm 3 and CLI radiance (r 2 5 0.83) and CLI radiance/ID (r 2 5 0.82). MLN4924 demonstrated a significant reduction in tumor volume after treatment (volume ratio of treated vs. control, 0.114 at day 29). Conclusion: The PET and CLI data presented confirm the correlation and dynamic sensitivity of this new imaging modality. CLI provides a preclinical alternative to expensive PET instrumentation. Future highthroughput studies should provide for quicker turnaround and higher cost-to-return benefits in the drug discovery process.

Targeted PET imaging strategy to differentiate malignant from inflamed lymph nodes in diffuse large B-cell lymphoma

“…In addition, the DLBCL mice in this study exhibited loss of body weight, splenomegaly, lymphadenopathy, low blood hemoglobin levels, elevated white blood cell counts, and decreased blood platelet counts, all of which accurately mimic the pathophysiological symptoms of human DLBCL (24). Many previous lymphoma PET imaging studies used xenograft lymphoma tumors in immunocompromised mice (39)(40)(41)(42). Our study conducted in this elaborate DLBCL mouse model more accurately simulates the clinical scenario than those studies.…”

Cerenkov radiation: a multi-functional approach for biological sciences

“…Excellent correlations were found between CLI and PET for the monitoring of cancer therapy [45]. Robertson et al used CLI and PET to compare the efficacy of MLN4924, a phase 2 oncology therapeutic [46]. The CLI data correlated well with PET and showed dynamic sensitivity.…”

Cerenkov Imaging

“…A wide variety of medically relevant radioisotopes, including 15 O, 13 N, 68 Ga, 89 Zr, 64 Cu, 225 Ac, 90 Y, 124 I, and 74 As, have subsequently been studied for CLI, showing that radioactivity correlated well with the light output (radiance) both in vitro and in vivo . It has been used to monitor cancer chemotherapy (Robertson, Germanos, Manfredi, Smith, & Silva, 2011; Xu et al, 2012) and radiotherapy using labeled peptides (Zhang et al, 2013), as well as to image the expression of genes (Jeong et al, 2011; Wolfs et al, 2014; Yang et al, 2012). In radiotherapy, CLI is particularly useful as it is able to image radio-tracers with electron or even α-particle emission, which cannot be imaged reasonably otherwise (Liu, Ren, et al, 2010; Ruggiero et al, 2010).…”