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, Waldenstroms 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.
Keywords: Proteasome inhibitor, marizomib, bortezomib, NF-κB, multiple myeloma, pharmacodynamics, combination therapy
Current Cancer Drug Targets
Title: Marizomib, a Proteasome Inhibitor for All Seasons: Preclinical Profile and a Framework for Clinical Trials
Volume: 11 Issue: 3
Author(s): G. K. Lloyd, M. A. Palladino, A. Younes, E. Valashi, M. A. Spear, C. M. Sloss, A. M. Roccaro, P. G. Richardson, F. Pajonk, H. Ovaa, Y. Oki, S. T.C. Neuteboom, C. P. Miller, D. J. McConkey, W. McBride, B. C. Potts, K. S. Lam, P. R. Jensen, M. Groll, I. M. Ghobrial, W. Fenical, J. C. Cusack, D. Chauhan, J. Chandra, B. Bonavida, C. Berkers, S. Baritaki, K. C. Anderson and M. X. Albitar
Affiliation:
Keywords: Proteasome inhibitor, marizomib, bortezomib, NF-κB, multiple myeloma, pharmacodynamics, combination therapy
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, Waldenstroms 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.
Export Options
About this article
Cite this article as:
K. Lloyd G., A. Palladino M., Younes A., Valashi E., A. Spear M., M. Sloss C., M. Roccaro A., G. Richardson P., Pajonk F., Ovaa H., Oki Y., T.C. Neuteboom S., P. Miller C., J. McConkey D., McBride W., C. Potts B., S. Lam K., R. Jensen P., Groll M., M. Ghobrial I., Fenical W., C. Cusack J., Chauhan D., Chandra J., Bonavida B., Berkers C., Baritaki S., C. Anderson K. and X. Albitar M., Marizomib, a Proteasome Inhibitor for All Seasons: Preclinical Profile and a Framework for Clinical Trials, Current Cancer Drug Targets 2011; 11 (3) . https://dx.doi.org/10.2174/156800911794519716
DOI https://dx.doi.org/10.2174/156800911794519716 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Insights on the Neuromodulatory Propensity of Selaginella (Sanjeevani) and its Potential Pharmacological Applications
CNS & Neurological Disorders - Drug Targets Nanoemulsions for Improved Efficacy of Phytotherapeutics- A Patent Perspective
Recent Patents on Nanotechnology Lymphocytes in Alzheimer’s Disease Pathology: Altered Signaling Pathways
Current Alzheimer Research Comprehensive Analysis Reveals GPRIN1 is a Potential Biomarker for Non-sm all Cell Lung Cancer
Current Bioinformatics Nanomedical Platform for Drug Delivery in Cancer
Current Organic Chemistry Targeting Epigenetics in Nervous System Disease
CNS & Neurological Disorders - Drug Targets Chemoradiation for Glioblastoma
Current Drug Therapy Radiolabeled Small Molecule Inhibitors of VEGFR - Recent Advances
Current Pharmaceutical Design STAT-3 Inhibitors: State of the Art and New Horizons for Cancer Treatment
Current Medicinal Chemistry G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function
Current Molecular Pharmacology Therapeutic Potential of Plant Extracts and Phytochemicals Against Brain Ischemia-Reperfusion Injury: A Review
The Natural Products Journal Pharmacology of Rhein and Advancement in the Synthesis of Its Derivatives
Current Traditional Medicine The University of New Mexico Center for Molecular Discovery
Combinatorial Chemistry & High Throughput Screening Heterocyclic Curcumin Derivatives of Pharmacological Interest: Recent Progress
Current Topics in Medicinal Chemistry Tropism-Modified Adenoviral and Adeno-Associated Viral Vectors for Gene Therapy
Current Gene Therapy Preliminary Analysis of Anti-proliferative, Apoptotic, and Anti-migratory Effects llw-3-6 in Skov-3 Ovarian Cystadenocarcinoma Cell Line
Letters in Drug Design & Discovery 1-O-Octadecyl-2-O-Methylglycero-3-phosphocholine (Edelfosine) and Cancer Cell Invasion: A Short Review
Anti-Cancer Agents in Medicinal Chemistry Sanguinarine: A Double-Edged Sword of Anticancer and Carcinogenesis and Its Future Application Prospect
Anti-Cancer Agents in Medicinal Chemistry Reviewing the Role of Resveratrol as a Natural Modulator of Microglial Activities
Current Pharmaceutical Design Perspectives of Fullerenes, Dendrimers, and Heterocyclic Compounds Application in Tumor Treatment
Recent Patents on Nanomedicine