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Journal of Clinical Oncology : Official... Jun 2024We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific...
PURPOSE
We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM).
METHODS
Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR).
RESULTS
Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time.
CONCLUSION
Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.
PubMed: 38879802
DOI: 10.1200/JCO.24.01008 -
The Journal of Biological Chemistry Jun 2024Chemotherapeutic agents for treating colorectal cancer primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system (UPS) is critical for apoptosis...
Chemotherapeutic agents for treating colorectal cancer primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system (UPS) is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of colorectal cancer. Among the DUBs, ubiquitin-specific protease 36 (USP36), is upregulated in colorectal cancer. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11 (K11)-linked ubiquitin chains from cIAP1 and lysine-48 (K48)-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-Smac complex and promotes RIPK1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in colorectal cancer progression and is a potential therapeutic target.
PubMed: 38876304
DOI: 10.1016/j.jbc.2024.107463 -
Expert Review of Hematology Jul 2024Cold agglutinin disease (CAD) is driven by IgM autoantibodies reactive at <37°C and able to fix complement. The activation of the classical complement pathway leads... (Review)
Review
INTRODUCTION
Cold agglutinin disease (CAD) is driven by IgM autoantibodies reactive at <37°C and able to fix complement. The activation of the classical complement pathway leads to C3-mediated extravascular hemolysis in the liver and to intravascular hemolytic crises in case of complement amplifying conditions. C3 positivity at direct Coombs test along with high titer agglutins are required for the diagnosis. Treatment is less standardized.
AREAS COVERED
This review recapitulates CAD diagnosis and then focus on the evolving management of the disease. Both current approach and novel targeted drugs are discussed. Literature search was conducted in PubMed and Scopus from 2000 to 2024 using 'CAD' and 'autoimmune hemolytic anemia' as keywords.
EXPERT OPINION
Rituximab represents the frontline approach in patients with symptomatic anemia or disabling cold-induced peripheral symptoms and is effective in 50-60% of cases. Refractory/relapsing patients are an unmet need and may now benefit from complement inhibitors, particularly the anti-C1s sutimlimab, effective in controlling hemolysis thus improving anemia in >80% of patients, but not active on cold-induced peripheral symptoms. Novel drugs include long-acting complement inhibitors, plasma cells, and B-cell targeting agents (proteasome inhibitors, anti-CD38, BTKi, PI3Ki, anti-BAFF). Combination therapy may be the future answer to CAD unmet needs.
Topics: Humans; Anemia, Hemolytic, Autoimmune; Algorithms; Rituximab; Disease Management; Autoantibodies; Antibodies, Monoclonal, Humanized; Immunoglobulin M
PubMed: 38872338
DOI: 10.1080/17474086.2024.2366540 -
Bioorganic & Medicinal Chemistry Jul 2024Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to...
Targeted protein degradation (TPD), employing proteolysis-targeting chimeras (PROTACs) composed of ligands for both a target protein and ubiquitin ligase (E3) to redirect the ubiquitin-proteasome system (UPS) to the target protein, has emerged as a promising strategy in drug discovery. However, despite the vast number of E3 ligases, the repertoire of E3 ligands utilized in PROTACs remains limited. Here, we report the discovery of a small-molecule degron with a phenylpropionic acid skeleton, derived from a known ligand of S-phase kinase-interacting protein 2 (Skp2), an E3 ligase. We used this degron to design PROTACs inducing proteasomal degradation of HaloTag-fused proteins, and identified key structural relationships. Surprisingly, our mechanistic studies excluded the involvement of Skp2, suggesting that this degron recruits other protein(s) within the UPS.
Topics: Humans; S-Phase Kinase-Associated Proteins; Small Molecule Libraries; Proteolysis; Phenylpropionates; Structure-Activity Relationship; Proteasome Endopeptidase Complex; Molecular Structure; Ligands; HEK293 Cells; Degrons
PubMed: 38870716
DOI: 10.1016/j.bmc.2024.117789 -
Plant Biotechnology Journal Jun 2024With global climate change, it is essential to find strategies to make crops more resistant to different stresses and guarantee food security worldwide. E3 ubiquitin... (Review)
Review
With global climate change, it is essential to find strategies to make crops more resistant to different stresses and guarantee food security worldwide. E3 ubiquitin ligases are critical regulatory elements that are gaining importance due to their role in selecting proteins for degradation in the ubiquitin-proteasome proteolysis pathway. The role of E3 Ub ligases has been demonstrated in numerous cellular processes in plants responding to biotic and abiotic stresses. E3 Ub ligases are considered a class of proteins that are difficult to control by conventional inhibitors, as they lack a standard active site with pocket, and their biological activity is mainly due to protein-protein interactions with transient conformational changes. Proteolysis-targeted chimeras (PROTACs) are a new class of heterobifunctional molecules that have emerged in recent years as relevant alternatives for incurable human diseases like cancer because they can target recalcitrant proteins for destruction. PROTACs interact with the ubiquitin-proteasome system, principally the E3 Ub ligase in the cell, and facilitate proteasome turnover of the proteins of interest. PROTAC strategies harness the essential functions of E3 Ub ligases for proteasomal degradation of proteins involved in dysfunction. This review examines critical advances in E3 Ub ligase research in plant responses to biotic and abiotic stresses. It highlights how PROTACs can be applied to target proteins involved in plant stress response to mitigate pathogenic agents and environmental adversities.
PubMed: 38864414
DOI: 10.1111/pbi.14407 -
American Journal of Hematology Jun 2024Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM)...
Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.
PubMed: 38856176
DOI: 10.1002/ajh.27382 -
Dalton Transactions (Cambridge, England... Jun 2024In order to investigate the structural features and antiproliferative activity of Pd(II) complexes containing halogenated ligands with different flexibility, several... (Comparative Study)
Comparative Study
Structural features and antiproliferative activity of Pd(II) complexes with halogenated ligands: a comparative study between Schiff base and reduced Schiff base complexes.
In order to investigate the structural features and antiproliferative activity of Pd(II) complexes containing halogenated ligands with different flexibility, several Schiff base and reduced Schiff base Pd(II) complexes, namely X1X2PicPd, X1X2PyPd, X1X2Pic(R)Pd, and X1X2Py(R)Pd (where X = X = Cl, Br and I; Pic: 2-picolylamine; Py = 2-(2-pyridyl)ethylamine), were synthesized and characterized by spectroscopic methods and, in the case of Br2PyPd, Cl2Py(R)Pd and ClBrPy(R)Pd, also by X-ray crystallography. The results of the X-ray crystallography showed that in both series of complexes the Pd(II) ion has a distorted square-planar geometry, although the coordination modes of the two ligands are different. In the Schiff base-type complexes the ligand acts as a tridentate chelate with NN'O donor atoms, whereas in the reduced Schiff base-type complexes the ligand acts as a bidentate chelate with NN' donor atoms. In both series of complexes, the chloride ions occupy the residual coordination sites of the Pd(II) ion. TD-DFT calculations were performed for a better understanding of the UV-Vis spectra. From these calculations it was found that the signal appearing at ∼400 nm in the complexes with reduced Schiff base ligands (X1X2Pic(R)Pd and X1X2Py(R)Pd) is mainly due to a HOMO → LUMO transition, while for the Schiff base complex ClBrPyPd the signal is due to a HOMO → LUMO+1 transition. For the complex I2PicPd, combinations of HOMO-4 → LUMO and HOMO-2 → LUMO transitions were found to be responsible for that signal. In regard to the biological activity profile, all complexes were first investigated as proteasome inhibitors by fluorometric methods. From these enzymatic assays, it emerged that they are good inhibitors with IC values in the low-micromolar range and that their inhibitory activity is strictly related to the presence of the metal ion. Subsequently they were also subjected to cell-based assays (the resazurin method) to assess their antiproliferative properties by using two leukemic cell lines, namely the drug-sensitive CCRF-CEM cell line and its multidrug-resistant sub-cell line CEM/ADR5000. In this test they displayed IC values in the sub-micromolar and low-micromolar range determined for a selected metal complex (Br2Pic(R)Pd) and ligand (Cl2Pic(R)), respectively. Moreover, docking studies were performed on the two expected molecular targets, proteasome and DNA, to shed light on the mechanisms of action of these types of Pd(II) complexes.
Topics: Schiff Bases; Humans; Palladium; Cell Proliferation; Ligands; Antineoplastic Agents; Coordination Complexes; Crystallography, X-Ray; Cell Line, Tumor; Halogenation; Molecular Structure; Drug Screening Assays, Antitumor; Models, Molecular
PubMed: 38855858
DOI: 10.1039/d4dt00132j -
Transplantation and Cellular Therapy Jun 2024Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently...
Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.
PubMed: 38852784
DOI: 10.1016/j.jtct.2024.06.001 -
Phytomedicine : International Journal... Aug 2024A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce...
BACKGROUND
A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear.
PURPOSE
We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors.
METHODS
Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured.
RESULTS
Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol: PTEN tumor cells were resistant to celastrol, while PTEN cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTEN CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTEN CCA cells. Disrupting the autophagic pathway in PTEN CCA cells enhanced the cytotoxic effect of celastrol.
CONCLUSION
PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTEN CCA.
Topics: Cholangiocarcinoma; Pentacyclic Triterpenes; PTEN Phosphohydrolase; Humans; Cell Line, Tumor; Bile Duct Neoplasms; Triterpenes; Molecular Docking Simulation; Tripterygium; Antineoplastic Agents, Phytogenic; Proteasome Endopeptidase Complex; Autophagy; Bortezomib
PubMed: 38851099
DOI: 10.1016/j.phymed.2024.155790 -
Bioorganic & Medicinal Chemistry Jun 2024In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which...
In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.
Topics: Humans; Proteasome Inhibitors; Glutamate Carboxypeptidase II; Antineoplastic Agents; Antigens, Surface; Structure-Activity Relationship; Molecular Structure; Drug Screening Assays, Antitumor; Small Molecule Libraries; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Male; Prostatic Neoplasms; Proteasome Endopeptidase Complex
PubMed: 38850999
DOI: 10.1016/j.bmc.2024.117773