scholarly journals Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shansa Pranami E. Jayaweera ◽  
Sacheela Prasadi Wanigasinghe Kanakanamge ◽  
Dharshika Rajalingam ◽  
Gayathri N. Silva
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Biochemical Properties ◽  
Regulatory Proteins ◽  
Toxicity Profile ◽  
The Us ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.

Proteasome inhibitors as therapeutics

2005 ◽  
Vol 41 ◽  
pp. 205-218
Author(s):  
Constantine S. Mitsiades ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Paul G. Richardson ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Drug Class ◽  
Proteasome Inhibitors ◽  
Cell Cycle Regulators ◽  
Current State ◽  
Intracellular Mechanism ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hodgkin's Lymphomas ◽  
Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

PROTEASOME INHIBITION IN MULTIPLE MYELOMA: Therapeutic Implication

2005 ◽  
Vol 45 (1) ◽  
pp. 465-476 ◽  
Author(s):  
Dharminder Chauhan ◽  
Teru Hideshima ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Protein Translation ◽  
26S Proteasome ◽  
Intracellular Protein ◽  
Cycle Growth ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade™), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.

scholarly journals Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3281-3290 ◽  
Author(s):  
Deborah J. Kuhn ◽  
Qing Chen ◽  
Peter M. Voorhees ◽  
John S. Strader ◽  
Kevin D. Shenk ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Proteasome Inhibitor ◽  
Hematologic Malignancies ◽  
Irreversible Inhibitor ◽  
Inhibition Of Proliferation ◽  
Mitochondrial Membrane Depolarization ◽  
Dependent Inhibition ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

AbstractThe proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.

The ubiquitin-proteasome pathway regulates lysosomal degradation of the growth hormone receptor and its ligand

2001 ◽  
Vol 29 (4) ◽  
pp. 488-493 ◽  
Author(s):  
P. van Kerkhof ◽  
G. J. Strous
Keyword(s):  
Growth Hormone ◽  
Proteasome Inhibitor ◽  
Growth Hormone Receptor ◽  
Proteasome Inhibitors ◽  
Plasma Membrane Protein ◽  
Lysosomal Degradation ◽  
Ubiquitin Proteasome Pathway ◽  
Gh Receptor ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The growth hormone (GH) receptor (GHR) is a mammalian plasma membrane protein whose internalization is mediated by the ubiquitin-proteasome pathway. GH internalization and degradation are inhibited when cells are treated with proteasome inhibitors. Here we show that a GHR truncated at residue 369 can enter the cells in the presence of a proteasome inhibitor, but that the subsequent lysosomal degradation of GH is blocked. Lysosomal inhibitors prolong the half-life of both receptor and ligand. Experiments with antibodies against different receptor tail sections show that degradation of the GHR cytosolic domain precedes degradation of the extracellular GH-binding domain. A possible role for the ubiquitin-proteasome pathway in the degradation of the receptor and ligand is discussed.

The Ubiquitin-Proteasome Pathway and Resistance Mechanisms Developed Against the Proteasomal Inhibitors in Cancer Cells

2020 ◽  
Vol 21 (13) ◽  
pp. 1313-1325
Author(s):  
Azmi Yerlikaya ◽  
Ertan Kanbur
Keyword(s):  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Pressure ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Background: The ubiquitin-proteasome pathway is crucial for all cellular processes and is, therefore, a critical target for the investigation and development of novel strategies for cancer treatment. In addition, approximately 30% of newly synthesized proteins never attain their final conformations due to translational errors or defects in post-translational modifications; therefore, they are also rapidly eliminated by the ubiquitin-proteasome pathway. Objective: Here, an effort was made to outline the recent findings deciphering the new molecular mechanisms involved in the regulation of ubiquitin-proteasome pathway as well as the resistance mechanisms developed against proteasome inhibitors in cell culture experiments and in the clinical trials. Results: Since cancer cells have higher proliferation rates and are more prone to translational errors, they require the ubiquitin-proteasome pathway for selective advantage and sustained proliferation. Therefore, drugs targeting the ubiquitin-proteasome pathway are promising agents for the treatment of both hematological and solid cancers. Conclusions: A number of proteasome inhibitors are approved and used for the treatment of advanced and relapsed multiple myeloma. Unfortunately, drug resistance mechanisms may develop very fast within days of the start of the proteasome inhibitor-treatment either due to the inherent or acquired resistance mechanisms under selective drug pressure. However, a comprehensive understanding of the mechanisms leading to the proteasome inhibitor-resistance will eventually help the design and development of novel strategies involving new drugs and/or drug combinations for the treatment of a number of cancers.

The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites

Parasitology ◽  
2005 ◽  
Vol 131 (1) ◽  
pp. 37-44 ◽  
Author(s):  
C. LINDENTHAL ◽  
N. WEICH ◽  
Y.-S. CHIA ◽  
V. HEUSSLER ◽  
M.-Q. KLINKERT
Keyword(s):  
Protein Degradation ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Protein Conjugates ◽  
Anti Cancer ◽  
Dividing Cells ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Further Development ◽  
Specific Peptide

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

Real-world treatment patterns and outcomes of triple-exposed multiple myeloma patients treated in community oncology practices in the United States.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18727-e18727
Author(s):  
Robert Smith ◽  
Mei Xue ◽  
Natalie Dorrow ◽  
Prateesh Varughese ◽  
Cosima Hogea ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Real World ◽  
Proteasome Inhibitors ◽  
Office Visit ◽  
The United States ◽  
Subsequent Treatment ◽  
Treatment Patterns ◽  
Duration Of Therapy ◽  
The Us

e18727 Background: Treatment for multiple myeloma (MM) over the past decade has significantly improved survival. In particular, 3 drug classes have altered the treatment paradigm for MM patients: proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies (anti-CD38s). Despite these advances, the majority of patients with MM will become refractory to PIs, IMiDs, and anti-CD38s, and limited evidence indicates these patients have poor outcomes. A retrospective study in the US showed that 275 patients treated at 14 academic institutions with prior exposure to a PI, IMiD, and anti-CD38 had median overall survival of 9.2 months. The aim of this study was to evaluate real-world treatment patterns and outcomes (duration of therapy and overall survival) of patients who had been treated with a PI, IMiD, and anti-CD38 in community practices in the US. Methods: This retrospective observational study was conducted using the Integra Connect (IC) database. The IC database includes electronic health data from structured and unstructured fields from 12 community practices on the East and West Coast of the US. Adult patients with ≥2 ICD-9/ICD-10 codes for MM on at least 2 separate dates, who received MM treatment between Jan 1, 2016, and Dec 31, 2019, with treatment history that included at least one PI, one IMiD, and one anti-CD38 (triple exposed), and initiated a subsequent line of therapy (s-LOT) after becoming triple exposed, were included. Duration of length of s-LOT was defined as number of days from start of s-LOT to last-day supply of s-LOT. Overall survival was defined as the length of time from start of s-LOT through death or the date of the last office visit. Results: A total of 501 patients were included in this analysis. The median age of patients was 64.9 years; 50% were male; 50% had commercial insurance. 82.8% of patients had ECOG 0 or 1 at diagnosis and had received a median of 3 prior lines of therapy (LOTs) before initiating s-LOT. Prior to initiating s-LOT, 91% had been exposed to bortezomib, 81% to carfilzomib, 94% to lenalidomide, 82% to pomalidomide, and 100% to daratumumab. In s-LOT, 95% received treatment that included same drug or same drug class (30% received bortezomib, 48% carfilzomib, 31% lenalidomide, 47% pomalidomide, and 31% daratumumab). The median duration of s-LOT was 78 days and median survival was 10.3 months (308 days) from initiation of s-LOT. Conclusions: For triple-class exposed patients, there is a lack of consensus on the most efficacious approach to subsequent treatment. The present study shows a significant amount of retreatment with previously used agents or classes among these patients with short duration of therapy and poor survival. As has been previously noted, new strategies and agents targeting novel aspects of MM are needed to improve outcomes for these patients. Disclosures: This study (213286) was sponsored by GlaxoSmithKline.

Abstract 37: Centrosome Destabilization Through the Ubiquitin-Proteasome Pathway Regulates Proplatelet Production

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kellie R Machlus ◽  
Prakrith Vijey ◽  
Thomas Soussou ◽  
Joseph E Italiano
Keyword(s):  
Protein Degradation ◽  
Proteasome Inhibitors ◽  
Aurora Kinase ◽  
Proteasome Activity ◽  
Major Pathway ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Proplatelet Formation

Background: Proteasome inhibitors such as bortezomib, a chemotherapeutic used to treat multiple myeloma, induce thrombocytopenia within days of initiation. The mechanism for this thrombocytopenia has been tied to data revealing that proteasome activity is essential for platelet formation. The major pathway of selective protein degradation uses ubiquitin as a marker that targets proteins for proteolysis by the proteasome. This pathway is previously unexplored in megakaryocytes (MKs). Objectives: We aim to define the mechanism by which the ubiquitin-proteasome pathway affects MK maturation and platelet production. Results: Pharmacologic inhibition of proteasome activity blocks proplatelet formation in megakaryocytes. To further characterize how this degradation was occurring, we probed distinct ubiquitin pathways. Inhibition of the ubiquitin-activating enzyme E1 significantly inhibited proplatelet formation up to 73%. In addition, inhibition of the deubiquitinase proteins UCHL5 and USP14 significantly inhibited proplatelet formation up to 83%. These data suggest that an intact ubiquitin pathway is necessary for proplatelet formation. Proteomic and polysome analyses of MKs undergoing proplatelet formation revealed a subset of proteins decreased in proplatelet-producing megakaryocytes, consistent with data showing that protein degradation is necessary for proplatelet formation. Specifically, the centrosome stabilizing proteins Aurora kinase (Aurk) A/B, Tpx2, Cdk1, and Plk1 were decreased in proplatelet-producing MKs. Furthermore, inhibition of AurkA and Plk1, but not Cdk1, significantly inhibited proplatelet formation in vitro over 83%. Conclusions: We hypothesize that proplatelet formation is triggered by centrosome destabilization and disassembly, and that the ubiquitin-proteasome pathway plays a crucial role in this transformation. Specifically, regulation of the AurkA/Plk1/Tpx2 pathway may be key in centrosome integrity and initiation of proplatelet formation. Determination of the mechanism by which the ubiquitin-proteasome pathway regulates the centrosome and facilitates proplatelet formation will allow us to design better strategies to target and reverse thrombocytopenia.

The Ubiquitin Proteasome Pathway from Bench to Bedside

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 220-225 ◽  
Author(s):  
Robert Z. Orlowski
Keyword(s):  
Phase I ◽  
Hematological Malignancies ◽  
Expression Profiles ◽  
Proteasome Inhibitors ◽  
Rational Approach ◽  
Significant Activity ◽  
Ubiquitin Proteasome Pathway ◽  
Gene And Protein Expression ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The validation of the ubiquitin-proteasome pathway as a target for therapy of hematological malignancies stands out as one salient example of the ability to translate laboratory-based findings from the bench to the bedside. Preclinical studies showed that proteasome inhibitors had significant activity against models of non-Hodgkin lymphoma and multiple myeloma, and identified some of the relevant mechanisms of action. These led to phase I through III trials of the first clinically available proteasome inhibitor, bortezomib, which confirmed its activity as a single agent in these diseases. Modulation of proteasome function was then found to be a rational approach to achieve both chemosensitization in vitro and in vivo, as well as to overcome chemotherapy resistance. Based on these findings, first-generation bortezomib-based regimens incorporating traditional chemotherapeutics such as alkylating agents, anthracyclines, immunomodulatory agents, or steroids have been evaluated, and many show promise of enhanced clinical anti-tumor efficacy. Further studies of the pro-and anti-apoptotic actions of proteasome inhibitors, and of their effects on gene and protein expression profiles, suggest that novel agents, such as those targeting the heat shock protein pathways, are exciting candidates for incorporation into these combinations. Phase I trials to test these concepts are just beginning, but have already shown some encouraging results. Finally, novel proteasome inhibitors are being developed with unique properties that may also have therapeutic applications. Taken together, these studies demonstrate the power of rational drug design and development to provide novel, effective therapies for patients with hematological malignancies.

scholarly journals Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3764
Author(s):  
Matthias Wirth ◽  
Markus Schick ◽  
Ulrich Keller ◽  
Jan Krönke
Keyword(s):  
Multiple Myeloma ◽  
Translational Regulation ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Organ Damage ◽  
Post Translational Modifications ◽  
Damage Repair ◽  
Ubiquitin Proteasome ◽  
New Treatments ◽  
Effective Drugs

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma.

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