18F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib

Abstract

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMycΔEμ gene insertion and the widely expressed H2-Ld-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.

Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma

“…4). In agreement with that, all three iMyc alleles collaborate effectively with enforced IL-6 expression (H2-L d -IL6 transgene) in malignant plasma-cell transformation [90, 91]. Indeed, the double-transgenic iMycIL-6 strains of mice provide a robust experimental model system characterized by short time to tumor onset and complete penetrance of the malignant phenotype (100 % tumor incidence) that is now available for preclinical studies on IL-6-targeted therapies in myeloma.…”

“…Transfer of the iMyc transgenes from the original, mixed genetic background of segregating C57BL/6 × 129/SvJ alleles to the C background resulted in hypersusceptibility to inflammation-induced PCT. One of the newly developed, double-transgenic strains of iMycIL-6 mice, which was investigated in greater depth, is prone to myeloma bone disease [91], a shortcoming of many previously developed GEMMs of human myeloma. We are currently employing this strain to continue with the IL-6 theme, which includes a study on the biological significance of autocrine versus paracrine sources of IL-6 in tumor development (Fig.…”

Adoptive B-cell transfer mouse model of human myeloma

“…These findings demonstrated that host priming (lethal vs. sub-lethal irradiation) is key for . Extra-medullary tumor load was modest ( Figure 1F) relative to mice harboring IL-6/MYC-driven PCNs for which comparable PET data were available [11]. In keeping with the large M-spikes presented in Figure 1E, the PET results indicated that the malignant PCs exhibit a myeloma-like preponderance for hematopoietic bone marrow.…”

“…Because our chief interest concerns improved preclinical modeling of myeloma, the followup investigations concentrated on the PCN-bearing mice. To evaluate tumor burden, tumor dissemination pattern and extent of extra-medullary disease, 18 F-FDG-PET imaging was used [11]. Extra-medullary tumor load was modest ( Figure 1F) relative to mice harboring IL-6/MYC-driven PCNs for which comparable PET data were available [11].…”

Preclinical animal models of multiple myeloma

“…43 Interestingly, 18 F-FDG-PET/CT imaging can be used to monitor tumor progression and response to treatment in this model. 44 Rearrangements of MYC are late progression events in MM that are found in B40% of advanced MM tumors and have welldefined roles in a number of tumor types. Early attempts at forcing MYC expression, such as those using the Em enhancer, which drives transgene expression throughout the B-cell development (Em-Myc transgenic model 45 ), resulted in the development of pre-germinal center lymphomas early in life.…”