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, che-motherapeutics 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.

Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

“…NPI-0052 is active against a variety of tumor cell types (40,41), including primary plasma cells from bortezomib-resistant patients with multiple myeloma. When NPI-0052 and bortezomib were compared head to head in xenograft studies using the twice-weekly (days 1 and 4) bortezomib clinical-dosing schedule, the activity of the 2 compounds was comparable in a multiple myeloma model (38,42), whereas bortezomib displayed better efficacy than NPI-0052 in a prostate cancer model (36).…”

Targeting the Proteasome in Melanoma

“…Bortezomib also led to a marked increase of the Camptothecin induced release of cytochrome C (a critical step in the mitochondrial pathway of apoptosis) that was not seen after melanoma cells incubation with KINK-1 (Amschler 2010). The second generation proteasome inhibitor Marizonib (NPI-0052 or salinosporamide A) seems also to sensitize prostate cancer and malignant melanoma cells to Cisplatinum (Potts 2011). Other agents that showed a synergistic effect on melanoma cells when combined with proteasome inhibitors are radiation therapy (Munshi 2004), Geldanamycin and Geldanamycin analogues (that target the Hsp 90 protein chaperone) (Bonvini 2001, Mimnaugh 2004, Banerji 2009), the Hsp70 inhibitors KNK-437 and Schisandrin-B (Yerlikaya 2010), Mistletoe Lectin-I and the PPAR-A agonist Rosiglitazone (Freudlsperger 2007), Gossypol (an inhibitor of the anti-apoptotic proteins Mcl-1/Bcl-2/Bcl-xL) (Wolter 2007) and the BH3 mimetic ABT-737 (inhibitor of Bcl-2/Bcl-X(L)/Bcl-w) (Miller 2009), the cytokines Interferon-alpha (Lesinski 2008, Lesinski 2009) and IL-29 (Guenterberg 2010), Bacitracin (a protein disulfide isomerase inhibitor) (Lovat 2008), Decitabine (a demethylating agent) (Halaban 2009), Fenretinide (a synthetic retinoid inducing endoplasmic reticulum stress) (Hill 2009), Evodiamine , GRP78-specific subtilase toxin (that inhibits GRP78, a vital unfolded protein response mediator) (Martin 2010) and newly developed SMAC-mimetics (Lecis 2010).…”

“…Other agents that showed a synergistic effect on melanoma cells when combined with proteasome inhibitors are radiation therapy (Munshi 2004), Geldanamycin and Geldanamycin analogues (that target the Hsp 90 protein chaperone) (Bonvini 2001, Mimnaugh 2004, Banerji 2009), the Hsp70 inhibitors KNK-437 and Schisandrin-B (Yerlikaya 2010), Mistletoe Lectin-I and the PPAR-A agonist Rosiglitazone (Freudlsperger 2007), Gossypol (an inhibitor of the anti-apoptotic proteins Mcl-1/Bcl-2/Bcl-xL) (Wolter 2007) and the BH3 mimetic ABT-737 (inhibitor of Bcl-2/Bcl-X(L)/Bcl-w) (Miller 2009), the cytokines Interferon-alpha (Lesinski 2008, Lesinski 2009) and IL-29 (Guenterberg 2010), Bacitracin (a protein disulfide isomerase inhibitor) (Lovat 2008), Decitabine (a demethylating agent) (Halaban 2009), Fenretinide (a synthetic retinoid inducing endoplasmic reticulum stress) (Hill 2009), Evodiamine , GRP78-specific subtilase toxin (that inhibits GRP78, a vital unfolded protein response mediator) (Martin 2010) and newly developed SMAC-mimetics (Lecis 2010). A combination of the new generation proteasome inhibitor Marizomib with histone deacetylase inhibitors was also tested in preclinical melanoma models, with not yet published results (Potts 2011). Proteasome inhibition also enhanced the effect of cell-mediated immunotherapies in melanoma animal models, such as dendritic cell-based immunization/activation (Schumacher 2006) and adoptive transfer of tumor-specific T lymphocytes (Seeger 2010, Jazirehi 2011.…”

Secondary Metabolites Produced by an Endophytic Fungus Pestalotiopsis sydowiana and Their 20S Proteasome Inhibitory Activities

“…To date, three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, have been approved by the US FDA. Furthermore, some proteasome inhibitors, including marizomib (salinosporamide A, NPI-0052) [8] and CEP-18770, have entered clinical trials. Among them, carfilzomib and marizomib are derived from natural substances produced by microorganisms.…”