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Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Posted: Monday, May 2, 2022
Another step in better understanding multiple myeloma, with an eye on an eventual cure, has been taken with a preclinical study of the inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS), a novel mechanism by which to target numerous steps in protein homeostasis in multiple myeloma cells. Sarah A. Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha, and colleagues described their work in Experimental Hematology & Oncology.
“GGDPS inhibitors disrupt Rab geranylgeranylation, which in turn results in perturbation of Rab-mediated protein trafficking, leading to accumulation of intracellular monoclonal protein, induction of endoplasmic reticulum stress, and apoptosis,” the team explained. Their selected GGDPS inhibitor, RAM2061, has demonstrated favorable pharmacokinetic properties and in vivo efficacy, they added, and their goal was to evaluate whether combination therapy with RAM2061 and a proteosome inhibitor—bortezomib—would result in enhanced disruption of the unfolded protein response and increase efficacy against multiple myeloma.
Isobologram analysis of cytotoxicity data revealed a synergistic effect when bortezomib and RAM2061 were applied to multiple myeloma cells sequentially. With such sequential timing, the team’s combination treatment “induced enhanced activation of immunogenic cell death pathway markers, slowed multiple myeloma tumor growth, and lengthened survival in a multiple myeloma xenograft model without evidence of off-target toxicity,” they shared. Concurrent treatment, though, was “primarily additive or mildly antagonistic.”
This work is the first to demonstrate the feasibility of combining GGDPS inhibition and proteosome inhibitor therapy in vivo and the combination’s increased efficacy, according to Dr. Holstein and co-investigators. The results should encourage future preclinical and clinical studies to test this novel strategy of disrupting the steps of protein homeostasis via several different mechanisms in multiple myeloma, they concluded.
Disclosure: For full disclosures of the study authors, please visit EHOonline.biomedcentral.com.
Experimental Hematology & Oncology
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