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Blood Advances Feb 2023Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is...
Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is associated with a poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. We found that relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1-activating enzyme (SAE1/UBA2) is associated with poor overall survival. Consistently, continuous treatment of MM cell lines with carfilzomib (CFZ) enhanced SUMO pathway activity. Treatment of MM cell lines with the SUMO E1-activating enzyme inhibitor subasumstat (TAK-981) showed synergy with CFZ in both CFZ-sensitive and CFZ-resistant MM cell lines, irrespective of the TP53 state. Combination therapy was effective in primary MM cells and in 2 murine MM xenograft models. Mechanistically, combination treatment with subasumstat and CFZ enhanced genotoxic and proteotoxic stress, and induced apoptosis was associated with activity of the prolyl isomerase PIN1. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel and potent strategy for the treatment of proteasome inhibitor-resistant MM.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Multiple Myeloma; Sumoylation; Proteasome Endopeptidase Complex; Apoptosis; Ubiquitin-Activating Enzymes; NIMA-Interacting Peptidylprolyl Isomerase
PubMed: 35917568
DOI: 10.1182/bloodadvances.2022007875 -
Journal of Clinical Oncology : Official... Dec 2020Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation... (Randomized Controlled Trial)
Randomized Controlled Trial
Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial.
PURPOSE
Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed.
PATIENTS AND METHODS
The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization.
RESULTS
Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 12.9 months; HR, 0.586; < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% 8.0%), vomiting (24.2% 4.3%), and diarrhea (23.2% 12.3%). There was no increase in new primary malignancies (5.2% 6.2%); rates of on-study deaths were 2.6% versus 2.2%.
CONCLUSION
Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.
Topics: Aged; Antineoplastic Agents; Boron Compounds; Double-Blind Method; Female; Glycine; Humans; Maintenance Chemotherapy; Male; Middle Aged; Multiple Myeloma; Placebos; Progression-Free Survival; Proteasome Inhibitors; Stem Cell Transplantation; Treatment Outcome
PubMed: 33021870
DOI: 10.1200/JCO.20.02060 -
Cancer Letters Jul 2023Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed...
Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed that ivermectin exerted anti-MM effects and significantly synergized with proteasome inhibitors in vitro and in vivo. Ivermectin alone exhibited mild anti-MM activity in vitro. Further investigation suggested that ivermectin inhibited proteasome activity in the nucleus by repressing the nuclear import of proteasome subunits, such as PSMB5-7 and PSMA3-4. Therefore, ivermectin treatment caused the accumulation of ubiquitylated proteins and the activation of the UPR pathway in MM cells. Furthermore, ivermectin treatment caused DNA damage and DNA damage response (DDR) signaling pathway activation in MM cells. Ivermectin and bortezomib exhibited synergized anti-MM activity in vitro. The dual-drug treatment resulted in synergistic inhibition of proteasome activity and increased DNA damage. An in vivo study using a human MM cell line xenograft mouse model showed that ivermectin and bortezomib efficiently repressed MM tumor growth in vivo, while the dual-drug treatment was well tolerated by experimental animals. Overall, our results demonstrated that ivermectin alone or cotreated with bortezomib might be promising in MM treatment.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Bortezomib; Multiple Myeloma; Proteasome Endopeptidase Complex; Ivermectin; Disease Models, Animal; Cell Line, Tumor; Antineoplastic Agents
PubMed: 37149018
DOI: 10.1016/j.canlet.2023.216218 -
Trends in Pharmacological Sciences Aug 2023Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma.... (Review)
Review
Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Mitochondria; Immunotherapy; Drug Resistance, Neoplasm
PubMed: 37344251
DOI: 10.1016/j.tips.2023.05.006 -
International Journal of Molecular... Oct 2021The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The... (Review)
Review
The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34769030
DOI: 10.3390/ijms222111595 -
Expert Opinion on Investigational Drugs Oct 2020Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic... (Review)
Review
INTRODUCTION
Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic options are therefore urgently needed; however, there have been various drug failures in late-stage clinical development. The proteasome represents a key target for anti-cancer therapy as successfully shown in multiple myeloma and other hematologic malignancies.
AREAS COVERED
This review article summarizes the preclinical and clinical development of proteasome inhibitors in the context of glioblastoma.
EXPERT OPINION
Early clinical trials with bortezomib ended with disappointing results, possibly because this agent does not cross the blood-brain barrier. In contrast to bortezomib and other proteasome inhibitors, marizomib is a novel drug that displays strong inhibitory properties on all enzymatic subunits of the proteasome and, most importantly, crosses the blood-brain barrier, making it a potentially very active novel agent against intrinsic brain tumors. While preclinical studies have demonstrated significant anti-glioma activity, its clinical benefit has yet to be proven. Exploiting the biological effects of proteasome inhibitors in combination with other therapeutic strategies may represent a key next step in their clinical development.
Topics: Animals; Antineoplastic Agents; Bortezomib; Brain Neoplasms; Drug Development; Glioblastoma; Humans; Lactones; Proteasome Inhibitors; Pyrroles
PubMed: 32746640
DOI: 10.1080/13543784.2020.1803827 -
Biomolecules Nov 2021The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome... (Review)
Review
The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. In this review, we discuss the structure of proteasome and how proteasome's proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.
Topics: Aging; Humans; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Folding; Proteolysis; Small Molecule Libraries
PubMed: 34944433
DOI: 10.3390/biom11121789 -
Cell Chemical Biology May 2023The Plasmodium falciparum proteasome constitutes a promising antimalarial target, with multiple chemotypes potently and selectively inhibiting parasite proliferation and...
The Plasmodium falciparum proteasome constitutes a promising antimalarial target, with multiple chemotypes potently and selectively inhibiting parasite proliferation and synergizing with the first-line artemisinin drugs, including against artemisinin-resistant parasites. We compared resistance profiles of vinyl sulfone, epoxyketone, macrocyclic peptide, and asparagine ethylenediamine inhibitors and report that the vinyl sulfones were potent even against mutant parasites resistant to other proteasome inhibitors and did not readily select for resistance, particularly WLL that displays covalent and irreversible binding to the catalytic β2 and β5 proteasome subunits. We also observed instances of collateral hypersensitivity, whereby resistance to one inhibitor could sensitize parasites to distinct chemotypes. Proteasome selectivity was confirmed using CRISPR/Cas9-edited mutant and conditional knockdown parasites. Molecular modeling of proteasome mutations suggested spatial contraction of the β5 P1 binding pocket, compromising compound binding. Dual targeting of P. falciparum proteasome subunits using covalent inhibitors provides a potential strategy for restoring artemisinin activity and combating the spread of drug-resistant malaria.
Topics: Humans; Antimalarials; Proteasome Endopeptidase Complex; Plasmodium; Artemisinins; Malaria, Falciparum; Proteasome Inhibitors
PubMed: 36963402
DOI: 10.1016/j.chembiol.2023.03.002 -
Molecules (Basel, Switzerland) Feb 2020The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in... (Review)
Review
The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular "machine." As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Glycine; Humans; Lactones; Molecular Targeted Therapy; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Proteostasis; Pyrroles
PubMed: 32033280
DOI: 10.3390/molecules25030671 -
Nature Communications Feb 2021Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact...
Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Bone and Bones; Bortezomib; Cell Line, Tumor; Cell Proliferation; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 4; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Histones; Humans; Male; Middle Aged; Multiple Myeloma; Nuclear Receptor Coactivator 3; Proteasome Inhibitors; Recurrence; Repressor Proteins; Signal Transduction; Survival Analysis; Translocation, Genetic; Xenograft Model Antitumor Assays
PubMed: 33589584
DOI: 10.1038/s41467-021-21386-y