Preclinical Imaging of Multiple Myeloma Therapy Response

Multiple myeloma (MM) is a debilitating hematologic malignancy of terminally differentiated plasma cells in the bone marrow (BM). Advances in therapeutic regimens and the use of autologous stem cell transplantation have significantly improved survival rates and quality of life in patients. However, the disease remains incurable, with shorter, successive remission cycles following relapse. To reduce systemic, off-target toxicity and improve quality of life, there is a need for improved stratification of responding patients. Identification of specific, noninvasive, imaging biomarkers that correlate to therapeutic efficacy is an attractive strategy for stratifying responding patients, since the use of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) is clinically established. Here, we have developed a strategy for imaging MM disease pathogenesis and response to clinically relevant therapeutics by studying the bidirectional interactions between the BM microenvironment and myeloma cells at the cellular, environmental, and anatomical levels. Specifically, we have validated imaging markers that identify BM and myeloma-specific behaviors through three specific aims: The first aim validated the use of the phenylalanine analog 18F-FDOPA for monitoring the uptake and efficacy of the DNA alkylating agent melphalan, which is used extensively in elderly, non-transplant eligible patients and in relapsed, refractory disease. 18F-FDOPA uptake was significantly reduced in melphalan-treated mice with orthotopic myeloma tumors, and was concordant with the established 18F-FDG-PET imaging. Immunohistochemistry was used to validate 18F-FDOPA uptake results. Importantly, expression of LAT1, which is known to mediate 18F-FDOPA and melphalan uptake, was visibly increased, although this may be a result of increased tumor vascularity. Our results suggest that 18F-FDOPA-PET can provide complementary imaging to 18F-FDG-PET for monitoring response to melphalan therapy and overall LAT1 expression in MM. The second aim assessed the specificity and sensitivity of the peptidomimetic near-infrared fluorophore LLP2A-Cy5 for imaging the expression of the activated conformation of the VLA-4 integrin on the surface of myeloma cells. LLP2A-Cy5 imaging was also used to study response to treatment with the proteasome inhibitor bortezomib, which forms the backbone of several front-line MM therapy strategies. Uptake of LLP2A-Cy5 was significantly reduced in bortezomib-treated mice bearing intramedullary tumors, indicating a reduction in the expression of activated VLA-4. These observations are concordant with the known downregulation of adhesion-mediated drug resistance and VLA-4 by bortezomib. Our results indicate the viability of using LLP2A-Cy5 near-infrared imaging for sensitive, longitudinal assessment of VLA-4 expression for monitoring bortezomib treatment response. Finally, the third aim validated the use of preclinical, multi-parametric MRI for studying changes in the BM in a diffuse infiltrative intramedullary tumor model. Longitudinal imaging of the BM in the femur and tibia demonstrated significant regional differences in T1-weighted contrast uptake and parametric T2 that correlated to changes in viable tumor burden following treatment with bortezomib. Hematoxylin and eosin staining (H&E) was used to validate the MRI observations. H&E showed complete diffuse infiltration of the BM in untreated animals, while bortezomib therapy caused the concentration of tumor burden near the epiphyseal plate of the distal femur and proximal tibia. These observations, in combination with MRI results, establish the use of preclinical MRI for studying effects of disease progression and therapy response on the BM in a longitudinal, noninvasive manner. In summary, these studies established a combination of qualitative observations and quantitative results in PET, optical, and MRI based strategies. Thus, this project has integrated a structured, multi-modal approach for assessing changes in tumor burden and monitoring therapy response at varying granular levels within the myeloma/BM interaction spectrum. Future studies would adapt this approach into different cell lines and tumor models

Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival

Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which is increasingly treatable but still incurable. In 90% of MM patients, severe osteolysis results from pathological interactions between MM cells and the bone microenvironment. Delineating specific molecules and pathways for their role in cancer supportive interactions in the BM is vital for developing new therapies. Very Late Antigen 4 (VLA4, integrin

Current Landscape of Breast Cancer Imaging and Potential Quantitative Imaging Markers of Response in ER-Positive Breast Cancers Treated with Neoadjuvant Therapy.

In recent years, neoadjuvant treatment trials have shown that breast cancer subtypes identified on the basis of genomic and/or molecular signatures exhibit different response rates and recurrence outcomes, with the implication that subtype-specific treatment approaches are needed. Estrogen receptor-positive (ER+) breast cancers present a unique set of challenges for determining optimal neoadjuvant treatment approaches. There is increased recognition that not all ER+ breast cancers benefit from chemotherapy, and that there may be a subset of ER+ breast cancers that can be treated effectively using endocrine therapies alone. With this uncertainty, there is a need to improve the assessment and to optimize the treatment of ER+ breast cancers. While pathology-based markers offer a snapshot of tumor response to neoadjuvant therapy, non-invasive imaging of the ER disease in response to treatment would provide broader insights into tumor heterogeneity, ER biology, and the timing of surrogate endpoint measurements. In this review, we provide an overview of the current landscape of breast imaging in neoadjuvant studies and highlight the technological advances in each imaging modality. We then further examine some potential imaging markers for neoadjuvant treatment response in ER+ breast cancers

Evaluation of primary breast cancers using dedicated breast PET and whole-body PET.

Metabolic imaging of the primary breast tumor with 18F-fluorodeoxyglucose ([18F]FDG) PET may assist in predicting treatment response in the neoadjuvant chemotherapy (NAC) setting. Dedicated breast PET (dbPET) is a high-resolution imaging modality with demonstrated ability in highlighting intratumoral heterogeneity and identifying small lesions in the breast volume. In this study, we characterized similarities and differences in the uptake of [18F]FDG in dbPET compared to whole-body PET (wbPET) in a cohort of ten patients with biopsy-confirmed, locally advanced breast cancer at the pre-treatment timepoint. Patients received bilateral dbPET and wbPET following administration of 186 MBq and 307 MBq [18F]FDG on separate days, respectively. [18F]FDG uptake measurements and 20 radiomic features based on morphology, tumor intensity, and texture were calculated and compared. There was a fivefold increase in SULpeak for dbPET (median difference (95% CI): 4.0 mL-1 (1.8-6.4 mL-1), p = 0.006). Additionally, spatial heterogeneity features showed statistically significant differences between dbPET and wbPET. The higher [18F]FDG uptake in dbPET highlighted the dynamic range of this breast-specific imaging modality. Combining with the higher spatial resolution, dbPET may be able to detect treatment response in the primary tumor during NAC, and future studies with larger cohorts are warranted

Current Landscape of Breast Cancer Imaging and Potential Quantitative Imaging Markers of Response in ER-Positive Breast Cancers Treated with Neoadjuvant Therapy.

In recent years, neoadjuvant treatment trials have shown that breast cancer subtypes identified on the basis of genomic and/or molecular signatures exhibit different response rates and recurrence outcomes, with the implication that subtype-specific treatment approaches are needed. Estrogen receptor-positive (ER+) breast cancers present a unique set of challenges for determining optimal neoadjuvant treatment approaches. There is increased recognition that not all ER+ breast cancers benefit from chemotherapy, and that there may be a subset of ER+ breast cancers that can be treated effectively using endocrine therapies alone. With this uncertainty, there is a need to improve the assessment and to optimize the treatment of ER+ breast cancers. While pathology-based markers offer a snapshot of tumor response to neoadjuvant therapy, non-invasive imaging of the ER disease in response to treatment would provide broader insights into tumor heterogeneity, ER biology, and the timing of surrogate endpoint measurements. In this review, we provide an overview of the current landscape of breast imaging in neoadjuvant studies and highlight the technological advances in each imaging modality. We then further examine some potential imaging markers for neoadjuvant treatment response in ER+ breast cancers

18F-FDG Dedicated Breast PET Complementary to Breast MRI for Evaluating Early Response to Neoadjuvant Chemotherapy.

Purpose To compare quantitative measures of tumor metabolism and perfusion using fluorine 18 (18F) fluorodeoxyglucose (FDG) dedicated breast PET (dbPET) and breast dynamic contrast-enhanced (DCE) MRI during early treatment with neoadjuvant chemotherapy (NAC). Materials and Methods Prospectively collected DCE MRI and 18F-FDG dbPET examinations were analyzed at baseline (T0) and after 3 weeks (T1) of NAC in 20 participants with 22 invasive breast cancers. FDG dbPET-derived standardized uptake value (SUV), metabolic tumor volume, and total lesion glycolysis (TLG) and MRI-derived percent enhancement (PE), signal enhancement ratio (SER), and functional tumor volume (FTV) were calculated at both time points. Differences between FDG dbPET and MRI parameters were evaluated after stratifying by receptor status, Ki-67 index, and residual cancer burden. Parameters were compared using Wilcoxon signed rank and Mann-Whitney U tests. Results High Ki-67 tumors had higher baseline SUVmean (difference, 5.1; P = .01) and SUVpeak (difference, 5.5; P = .04). At T1, decreases were observed in FDG dbPET measures (pseudo-median difference T0 minus T1 value [95% CI]) of SUVmax (-6.2 [-10.2, -2.6]; P < .001), SUVmean (-2.6 [-4.9, -1.3]; P < .001), SUVpeak (-4.2 [-6.9, -2.3]; P < .001), and TLG (-29.1 mL3 [-71.4, -6.8]; P = .005) and MRI measures of SERpeak (-1.0 [-1.3, -0.2]; P = .02) and FTV (-11.6 mL3 [-22.2, -1.7]; P = .009). Relative to nonresponsive tumors, responsive tumors showed a difference (95% CI) in percent change in SUVmax of -34.3% (-55.9%, 1.5%; P = .06) and in PEpeak of -42.4% (95% CI: -110.5%, 8.5%; P = .08). Conclusion 18F-FDG dbPET was sensitive to early changes during NAC and provided complementary information to DCE MRI that may be useful for treatment response evaluation. Keywords: Breast, PET, Dynamic Contrast-enhanced MRI Clinical trial registration no. NCT01042379 Supplemental material is available for this article. © RSNA, 2024