Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026764 (
multiple myeloma
)
36,148
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Multiple myeloma
(MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-
18
F-fluoro-l-
phenylalanine
(
18
F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM.
Methods:
C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic
18
F-FDG and
18
F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUV
max
, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression.
Results:
Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both
18
F-FDG and
18
F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in
18
F-FDG and
18
F-FDOPA uptake, with an increase in
18
F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar.
Conclusion:
18
F-FDOPA PET/CT complemented
18
F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM.
18
F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.
...
PMID:Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with
18
F-FDOPA and
18
F-FDG PET. 2970 Jan 26
Drug resistance remains a critical problem for the treatment of
multiple myeloma
(MM), which can serve as a specific example for a highly prevalent unmet medical need across almost all cancer types. In MM, the therapeutic arsenal has expanded and diversified, yet we still lack in-depth molecular understanding of drug mechanisms of action and cellular pathways to therapeutic escape. For those reasons, preclinical models of drug resistance are developed and characterized using different approaches to gain insights into tumor biology and elucidate mechanisms of drug resistance. For MM, numerous drugs are used for treatment, including conventional chemotherapies (e.g., melphalan or L-
phenylalanine
nitrogen mustard), proteasome inhibitors (e.g., Bortezomib), and immunomodulators (e.g., Lenalidomide). These agents have diverse effects on the
myeloma
cells, and several mechanisms of drug resistance have been previously described. The disparity of these mechanisms and the complexity of these biological processes lead to the formation of complicated hypotheses that require omics approaches for efficient and effective analysis of model systems that can then be interpreted for patient benefit. Here, we describe the combination of metabolomics and proteomics to assess melphalan resistance in MM by examining three specific areas: drug metabolism, modulation of endogenous metabolites to assist in therapeutic escape, and changes in protein activity gauged by ATP probe uptake.
...
PMID:Proteometabolomics of Melphalan Resistance in Multiple Myeloma. 3112 62
<< Previous
1
2
3
4
5
6
7
