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Science (New York, N.Y.) Feb 2021The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding-deficient...
The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding-deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which we named "anisosomes", have shells that exhibit birefringence, thus indicating liquid crystal formation. Guided by mathematical modeling, we identified the primary components of the liquid core to be HSP70 family chaperones, whose adenosine triphosphate (ATP)-dependent activity maintained the liquidity of shells and cores. In vivo proteasome inhibition within neurons, to mimic aging-related reduction of proteasome activity, induced TDP-43-containing anisosomes. These structures converted to aggregates when ATP levels were reduced. Thus, acetylation, HSP70, and proteasome activities regulate TDP-43 phase separation and conversion into a gel or solid phase.
Topics: Aging; Animals; Anisotropy; Cryoelectron Microscopy; DNA-Binding Proteins; HEK293 Cells; HSP70 Heat-Shock Proteins; Histone Deacetylases; Humans; Liquid Crystals; Mice; Mice, Inbred C57BL; Mutation; Neurodegenerative Diseases; Neurons; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Aggregates; Protein Domains; RNA-Binding Proteins; Rats; Rats, Sprague-Dawley
PubMed: 33335017
DOI: 10.1126/science.abb4309 -
Frontiers in Immunology 2020Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral... (Review)
Review
Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) neurons cell body (neuronopathy/ganglionopathy). In addition, antineoplastic treatments may affect the blood brain barrier integrity, leading to cognitive impairment that may be severe and long-lasting. CIPN may affect patient quality of life leading to modification or discontinuation of the anticancer therapy. Although the mechanisms of the damage are not completely understood, several hypotheses have been proposed, among which neuroinflammation is now emerging to be relevant in CIPN pathophysiology. In this review, we consider different aspects of neuro-immune interactions in several CIPN preclinical studies which suggest a critical connection between chemotherapeutic agents and neurotoxicity. The features of the neuroinflammatory processes may be different depending on the type of drug (platinum derivatives, taxanes, vinca alkaloids and proteasome inhibitors). In particular, recent studies have demonstrated an involvement of the immune response (both innate and adaptive) and the stimulation and secretion of mediators (cytokines and chemokines) that may be responsible for the painful symptoms, whereas glial cells such as satellite and Schwann cells might contribute to the maintenance of the neuroinflammatory process in DRG and axons respectively. Moreover, neuroinflammatory components have also been shown in the spinal cord with microglia and astrocytes playing an important role in CIPN development. Taking together, better understanding of these aspects would permit the development of possible strategies in order to improve the management of CIPN.
Topics: Antineoplastic Agents; Chemokines; Cisplatin; Cognitive Dysfunction; Cytokines; Humans; Inflammation; Neoplasms; Neuralgia; Neuroimmunomodulation; Peripheral Nervous System Diseases; Proteasome Inhibitors; Quality of Life; Signal Transduction; Taxoids; Vinca Alkaloids
PubMed: 33613570
DOI: 10.3389/fimmu.2020.626687 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2022Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for... (Review)
Review
Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Proteasome Inhibitors
PubMed: 35148975
DOI: 10.1016/j.clml.2022.01.011 -
Blood Cancer Journal Mar 2022The current standard of care model for newly diagnosed fit multiple myeloma (NDMM) patients is the sequential treatment of induction, high dose melphalan, autologous... (Review)
Review
The current standard of care model for newly diagnosed fit multiple myeloma (NDMM) patients is the sequential treatment of induction, high dose melphalan, autologous stem cell transplantation (ASCT), and maintenance. Adequate induction is required to achieve good disease control and induce deep response rates while minimizing toxicity as a bridge to transplant. Doublet induction regimens have greatly fallen out of favor, with current international guidelines favoring triplet or quadruplet induction regimens built around the backbone of the proteasome inhibitor bortezomib and dexamethasone (Vd). In fact, the updated 2021 European Haematology Association (EHA) and European Society for Medical Oncology (ESMO) clinical practice guidelines recommend the use of either lenalidomide-Vd (VRd), or daratumumab-thalidomide-Vd (Dara-VTd) as first-line options for transplant-eligible NDMM patients, and when not available, thalidomide-Vd (VTd) or cyclophosphamide-Vd (VCd) as acceptable alternatives. Quadruplet regimens featuring anti-CD38 monoclonal antibodies are extremely promising and remain heavily investigated, as is the incorporation of more recent proteasome inhibitors such as carfilzomib. This review will focus on induction therapies prior to ASCT examining the latest data and guidelines on triplet and quadruplet regimens.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Multiple Myeloma; Proteasome Inhibitors; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous
PubMed: 35347107
DOI: 10.1038/s41408-022-00645-1 -
Nature Communications Mar 2023Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be...
Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.
Topics: Humans; Bortezomib; Multiple Myeloma; Proteasome Inhibitors; Drug Resistance, Neoplasm; Cell Line, Tumor; Transcription Factors; Antineoplastic Agents; Proteasome Endopeptidase Complex
PubMed: 36894562
DOI: 10.1038/s41467-023-37013-x -
Neuromuscular Disorders : NMD Feb 2020Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic... (Review)
Review
Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic treatment, immunosuppressive drugs and thymectomy. Corticosteroids remain the cornerstone of treatment beside symptomatic medication due to their low cost, wide availability and fast mode of action. However, long term steroid use carries substantial risks of severe adverse side effects. Therefore, non-steroidal immunosuppressive drugs are commonly added to the treatment. Unfortunately, they have a delayed-onset effect and evidence of their efficacy appears to be difficult to obtain. Several trials using drugs that have had clear positive results in other immunological disorders have failed in myasthenia. This failure may in part be related to difficulties in the design of clinical trial for myasthenia, which has a fluctuating disease course involving weakness that may be difficult to assess quantitively. This problem is exacerbated by the tendency of most clinical trials to select patients with a stable, but severe disease. Future trials should: select patients with weakness and fatigability that is completely explained by their myasthenia gravis, use a design that avoids the exclusion of patients with recent changes in medication, and explore the possibilities to completely avoid the use of corticosteroids.
Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Exercise Therapy; Humans; Immunosuppressive Agents; Myasthenia Gravis; Proteasome Inhibitors; Thymectomy
PubMed: 32007304
DOI: 10.1016/j.nmd.2019.12.003 -
The Lancet. Oncology Oct 2020Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in... (Randomized Controlled Trial)
Randomized Controlled Trial
Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial.
BACKGROUND
Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT).
METHODS
In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1-8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1-14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1-21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing.
FINDINGS
Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5-23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8-37·8) in the KRd group and 34·4 months (30·1-not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83-1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3-4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [<1%]), dyspnoea (nine [2%] vs 38 [7%]), and thromboembolic events (11 [2%] vs 26 [5%]). Treatment-related deaths occurred in two patients (<1%) in the VRd group (one cardiotoxicity and one secondary cancer) and 11 (2%) in the KRd group (four cardiotoxicity, two acute kidney failure, one liver toxicity, two respiratory failure, one thromboembolic event, and one sudden death).
INTERPRETATION
The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs.
FUNDING
US National Institutes of Health, National Cancer Institute, and Amgen.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Intention to Treat Analysis; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Oligopeptides; Proteasome Inhibitors; Treatment Outcome
PubMed: 32866432
DOI: 10.1016/S1470-2045(20)30452-6 -
Biomolecules Dec 2021Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory... (Review)
Review
Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases.
Topics: Animals; Antineoplastic Agents; Bortezomib; Mammals; Multiple Myeloma; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis
PubMed: 35053202
DOI: 10.3390/biom12010054 -
Kidney360 Mar 2023Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma...
Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.
Topics: Humans; Thrombotic Microangiopathies; Antineoplastic Agents; Neoplasms; Gemcitabine; Proteasome Inhibitors
PubMed: 36706238
DOI: 10.34067/KID.0000000000000061 -
PLoS Pathogens Dec 2021Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all... (Review)
Review
Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
Topics: Animals; Chagas Disease; Humans; Leishmaniasis; Mycobacterium tuberculosis; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34882737
DOI: 10.1371/journal.ppat.1010058