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Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

ABSTRACT: The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

SUBMITTER: Potts BC

PROVIDER: S-EPMC3712795 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

Potts B C BC Albitar M X MX Anderson K C KC Baritaki S S Berkers C C Bonavida B B Chandra J J Chauhan D D Cusack J C JC Fenical W W Ghobrial I M IM Groll M M Jensen P R PR Lam K S KS Lloyd G K GK McBride W W McConkey D J DJ Miller C P CP Neuteboom S T C ST Oki Y Y Ovaa H H Pajonk F F Richardson P G PG Roccaro A M AM Sloss C M CM Spear M A MA Valashi E E Younes A A Palladino M A MA

Current cancer drug targets 20110301 3

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activit ...[more]

PMID: 21247382

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Project description:Salinosporamide A (NPI-0052, marizomib) is a naturally occurring proteasome inhibitor derived from the marine actinobacterium Salinispora tropica, and represents a promising clinical agent in the treatment of hematologic malignancies. Recently, these actinobacteria were shown to harbor self-resistance properties to salinosporamide A by expressing redundant catalytically active mutants of the 20S proteasome β-subunit, reminiscent of PSMB5 mutations identified in cancer cells with acquired resistance to the founding proteasome inhibitor bortezomib (BTZ). Here, we assessed the growth inhibitory potential of salinosporamide A in human acute lymphocytic leukemia CCRF-CEM cells, and its 10-fold (CEM/BTZ7) and 123-fold (CEM/BTZ200) bortezomib-resistant sublines harboring PSMB5 mutations. Parental cells displayed sensitivity to salinosporamide A (IC50 = 5.1 nM), whereas their bortezomib-resistant sublines were 9- and 17-fold cross-resistant to salinosporamide A, respectively. Notably, combination experiments of salinosporamide A and bortezomib showed synergistic activity in CEM/BTZ200 cells. CEM cells gradually exposed to 20 nM salinosporamide A (CEM/S20) displayed stable 5-fold acquired resistance to salinosporamide A and were 3-fold cross-resistant to bortezomib. Consistent with the acquisition of a PSMB5 point mutation (M45V) in CEM/S20 cells, salinosporamide A displayed a markedly impaired capacity to inhibit β5-associated catalytic activity. Last, compared with parental CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulation of constitutive proteasome subunits, while retaining unaltered immunoproteasome subunit expression. In conclusion, salinosporamide A displayed potent antileukemic activity against bortezomib-resistant leukemia cells. β-Subunit point mutations as a common feature of acquired resistance to salinosporamide A and bortezomib in hematologic cells and S. tropica suggest an evolutionarily conserved mechanism of resistance to proteasome inhibitors.

Project description:PET is used to measure tau protein accumulation in Alzheimer's disease. Multiple biomarkers have been proposed to track disease progression, most notably the standardized uptake value ratio of PET tracer uptake in a target region of interest relative to a reference region, but literature suggests these region choices are nontrivial. This study presents and evaluates a novel framework, BioDisCVR, designed to facilitate the discovery of useful biomarkers, demonstrated on [18F]AV-1451 tau PET data in multiple cohorts. BioDisCVR enhances signal-to-noise by conducting a data-driven search through the space of possible combinations of regional tau PET signals into a ratio of two composite regions, driven by a user-defined fitness function. This study compares ratio-based biomarkers discovered by the framework with state-of-the-art standardized uptake value ratio biomarkers. Data used is tau PET regional measurements from 198 individuals from the Alzheimer's Disease Neuroimaging Initiative database, used for discovery, and 42 from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging (MCSA), used for external validation. Biomarkers are evaluated by calculating clinical trial sample size estimates for 80% power and 20% effect size. Secondary metrics are a measure of longitudinal consistency (standard deviation of linear mixed-effects model residuals), and separation between cognitive groups (t-statistic of the change over time due to being cognitively impaired). When applied to preclinical (secondary prevention with CU individuals) and clinical (treatment aimed at cognitively impaired individuals) trials on Alzheimer's disease, our data-driven framework BioDisCVR discovered ratio-based tau PET biomarkers vastly superior to previous work, both reducing measurement error and sample size estimates for hypothetical clinical trials. Our analysis suggests remarkable potential for patient benefit (reduced exposure to health risks associated with experimental drugs) and substantial cost savings, through accelerated trials and reduced sample sizes. Our study supports the leveraging of data-driven methods like BioDisCVR for clinical benefit, with the potential to positively impact drug development in Alzheimer's disease and beyond.

Dataset Information

Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

Publications

Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

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