150 results found
Almada LL, Barroso K, Sen S, et al., 2023, GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1., Biochim Biophys Acta Gene Regul Mech, Vol: 1866
Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.
Lecat CSY, Fisher A, Atta M, et al., 2023, High patient satisfaction and increased physical activity following a remote multidisciplinary team multiple myeloma clinic, Supportive Care in Cancer, Vol: 31, Pages: 1-10, ISSN: 0941-4355
PurposePatients with multiple myeloma suffer from disease-related complications such as bone destruction, toxicities from repeated therapies and age-related co-morbidities. With improved treatment options, patients are living longer and have specific survivorship needs such as low exercise levels that need to be addressed. In this study, we designed, implemented and evaluated a multidisciplinary team (MDT) myeloma clinic that provided participants with tailored exercise and lifestyle advice.MethodsThe Promoting Individualised Self-Management and Survivorship (PrISMS) clinic was set up in two UK myeloma centres. This remote MDT clinic comprised of a doctor, a nurse specialist and a physiotherapist. Patients were required to complete blood tests and a questionnaire about their symptoms and concerns before each consultation. Patient-reported outcome measures were captured using validated questionnaires. Patient feedback was collected using a specially designed survey and structured telephone interviews.ResultsSixty-one patients were enrolled in the pilot clinic with 210 consultations held during the study period. Nine patients had disease progression and were referred safely back to face-to-face clinics. There was a significant improvement in patients’ exercise score (p = 0.02) after PrISMS clinic. Patient satisfaction was high, with 83% feeling more confident in self-managing myeloma after PrISMS clinic.ConclusionPrISMS clinic is safe and feasible, with high patient compliant and acceptability. It empowers patients to self-manage their condition and encourages physical activity, which is associated with improved quality of life and fatigue level. Future randomised controlled trials will help to confirm its benefits on patient clinical outcomes and cost-effectiveness.
Royle K-L, Coulson AB, Ramasamy K, et al., 2022, Risk and response adapted therapy following autologous stem cell transplant in patients with newly diagnosed multiple myeloma (RADAR (UK-MRA Myeloma XV Trial): study protocol for a phase II/III randomised controlled trial, BMJ OPEN, Vol: 12, ISSN: 2044-6055
Kendall J, Hall A, Roberts S, et al., 2022, MUKtwelve protocol: a phase II randomised, controlled, open, parallel group, multicentre trial of selinexor, cyclophosphamide and prednisolone (SCP) versus cyclophosphamide and prednisolone (CP) in patients with relapsed or refractory multiple myeloma, BMJ OPEN, Vol: 12, ISSN: 2044-6055
ElGendy K, Barwick T, Auner HW, et al., 2022, Repeatability and test-retest reproducibility of mean apparent diffusion coefficient measurements of focal and diffuse disease in relapsed multiple myeloma at 3t whole body diffusion weighted MRI (WB-DW-MRI), The British Journal of Radiology, Vol: 95, ISSN: 0007-1285
Objectives:To assess the test-retest reproducibility and intra/inter observer agreement of Apparent Diffusion Coefficient (ADC) measurements of myeloma lesions using WB-DW-MRI at 3T MRI.Methods:Following ethical approval, eleven consenting patients with relapsed multiple myeloma were prospectively recruited and underwent baseline WB-DW-MRI. For a single bed position, axial DWI was repeated after a short interval to permit test- retest measurements.Mean ADC measurement was performed by two experienced observers. Intra and inter observer agreement and test-retest reproducibility were assessed, using coefficient of variation (CV) and interclass correlation coefficient (ICC) measures, for diffuse and focal lesions (small ≤10 mm and large >10 mm).Results:Forty seven sites of disease were outlined (23 focal, 24 diffuse) in different bed positions (pelvis = 22, thorax = 20, head and neck = 5). For all lesions, there was excellent intra observer agreement with ICC of 0.99 (0.98–0.99) and COV of 5%. For inter observer agreement, ICC was 0.89 (0.8–0.934) and COV was 17%. There was poor inter observer agreement for diffuse (ICC = 0.46) and small lesions (ICC = 0.54).For test-retest reproducibility, excellent ICC (0.916) and COV (14.5%) values for mean ADC measurements were observed. ICCs of test-retest were similar between focal lesions (0.83) and diffuse infiltration (0.80), while ICCs were higher in pelvic (0.95) compared to thoracic (0.81) region and in small (0.96) compared to large (0.8) lesions.Conclusions:ADC measurements of focal lesions in multiple myeloma are repeatable and reproducible, while there is more variation in ADC measurements of the diffuse disease in patients with multiple myeloma.Advances in knowledge:Mean ADC measurements are repeatable and reproducible in focal lesions in multiple myeloma, while the ADC measurements of diffuse disease in multiple myeloma are more subject to variation. The evidence supports the future pot
Roman-Trufero M, Auner HW, Edwards CM, 2022, Multiple myeloma metabolism - a treasure trove of therapeutic targets?, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Multiple myeloma is an incurable cancer of plasma cells that is predominantly located in the bone marrow. Multiple myeloma cells are characterized by distinctive biological features that are intricately linked to their core function, the assembly and secretion of large amounts of antibodies, and their diverse interactions with the bone marrow microenvironment. Here, we provide a concise and introductory discussion of major metabolic hallmarks of plasma cells and myeloma cells, their roles in myeloma development and progression, and how they could be exploited for therapeutic purposes. We review the role of glucose consumption and catabolism, assess the dependency on glutamine to support key metabolic processes, and consider metabolic adaptations in drug-resistant myeloma cells. Finally, we examine the complex metabolic effects of proteasome inhibitors on myeloma cells and the extracellular matrix, and we explore the complex relationship between myeloma cells and bone marrow adipocytes.
Auner HW, Brown SR, Walker K, et al., 2022, Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results, BLOOD CANCER JOURNAL, Vol: 12, ISSN: 2044-5385
- Author Web Link
- Citations: 4
Benjamin R, Garg M, Basu S, et al., 2022, Outcomes of Patients (pts) with Previously Treated Multiple Myeloma (MM) from European Countries and the United Kingdom, Treated with Selinexor, Bortezomib and Dexamethasone (XVd) Versus Bortezomib and Dexamethasone (Vd): A Post Hoc Analysis from the BOSTON Trial, Publisher: WILEY, Pages: 127-128, ISSN: 0007-1048
Trasanidis N, Katsarou A, Ponnusamy K, et al., 2022, Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma, BLOOD, Vol: 139, Pages: 1939-1953, ISSN: 0006-4971
- Author Web Link
- Citations: 6
Ponnusamy K, Tzioni MM, Begum M, et al., 2022, The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma, HAEMATOLOGICA, Vol: 107, Pages: 721-732, ISSN: 0390-6078
- Author Web Link
- Citations: 5
Delimpasi S, Mateos MV, Auner HW, et al., 2021, Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 97, Pages: E83-E86, ISSN: 0361-8609
- Author Web Link
- Citations: 2
Klionsky DJ, 2021, Look youse guys and gals, dat just ain't right., Autophagy, Vol: 17, Pages: 3895-3896
When I invite authors to submit a punctum to Autophagy, my e-mail includes the following: "Note for international authors: I would like to point out that I personally edit all the puncta for accuracy, but also for English grammar and spelling. I make this point to all international authors as I do not want you to worry extensively about the writing. As a native English speaker, it is easy for me to make small changes of this nature." I do not claim to be an expert in English grammar; however, I am indeed a native English speaker, I read a lot, and I am even fond of using the dictionary (both hard copy and online). Also, I do a lot of editing. Thus, I thought I would share some common mistakes to help reduce the required edits for papers that are submitted to Autophagy.
Jagannath S, Facon T, Badros AZ, et al., 2021, Clinical Outcomes in Patients (Pts) with Dose Reduction of Selinexor in Combination with Bortezomib, and Dexamethasone (XVd) in Previously Treated Multiple Myeloma from the Boston Study, Publisher: AMER SOC HEMATOLOGY, Pages: 3793-+, ISSN: 0006-4971
Bahlis NJ, Richard S, White DJ, et al., 2021, Effects of Cytogenetic Risk on Outcomes in Multiple Myeloma Treated with Selinexor, Bortezomib, and Dexamethasone (XVd), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Chavda SJ, Galas-Filipowicz D, Fitzsimons E, et al., 2021, Autophagy Blockade Disrupts Myeloma Cell Recovery from Proteasome Inhibition and Enhances Apoptosis, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Yong KL, Hinsley S, Auner HW, et al., 2021, Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multi-centre, phase II, randomized, controlled trial (MUKfive), Haematologica: the hematology journal, Vol: 106, Pages: 2694-2706, ISSN: 0390-6078
The proteasome inhibitors (PIs), carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these PIs in combination with cyclophosphamide and dexamethasone (KCd vs VCd) in second line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomised patients (2:1) to KCd (201) or VCd (99); responding patients on carfilzomib were randomised to maintenance carfilzomib (69) or no further treatment (72). Primary endpoints were (i) very good partial response (VGPR, non-inferiority, OR 0.8) at 24 weeks, and (ii) progression-free survival (PFS). More participants achieved ≥VGPR with carfilzomib compared to bortezomib (40.2% vs. 31.9%, OR=1.48, 90%CI:0.95,2.31; non-inferior), with a trend for particular benefit in adverse risk disease. KCd was associated with higher overall response (≥PR, 84.0% vs. 68.1%, OR=2.72, 90%CI:1.62,4.55, p=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, p.
Sanchez L, Leleu X, Beaumont JL, et al., 2021, Peripheral neuropathy symptoms, pain, and functioning in previously treated multiple myeloma patients treated with selinexor, bortezomib, and dexamethasone, American Journal of Hematology, Vol: 96, Pages: E383-E386, ISSN: 0361-8609
Karadimitris A, 2021, Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma, Nature Communications, Vol: 12, Pages: 1-16, ISSN: 2041-1723
Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myelomainitiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.
Richard S, Chari A, Delimpasi S, et al., 2021, Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 96, Pages: 1120-1130, ISSN: 0361-8609
- Author Web Link
- Citations: 6
Mateos MV, Gavriatopoulou M, Facon T, et al., 2021, Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma, Journal of Hematology and Oncology, Vol: 14, ISSN: 1756-8722
Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.
Leleu X, Mateos M-V, Jagannath S, et al., 2021, Effects of refractory status to lenalidomide on safety and efficacy of selinexor, bortezomib, and dexamethasone (XVd) versus bortezomib and dexamethasone (Vd) in patients with previously treated multiple myeloma., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Facon T, Auner HW, Gavriatopoulou M, et al., 2021, Survival among older patients with previously treated multiple myeloma treated with selinexor, bortezomib, and dexamethasone (XVd) in the BOSTON study., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Auner HW, Gavriatopoulou M, Delimpasi S, et al., 2021, Effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 96, Pages: 708-718, ISSN: 0361-8609
- Author Web Link
- Citations: 9
Saavedra-Garcia P, Roman-Trufero M, Al-Sadah HA, et al., 2021, Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs, Proceedings of the National Academy of Sciences of USA, Vol: 118, ISSN: 0027-8424
Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known.Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stressresolution in multiple myeloma cells recovering from proteasome inhibition. Our observations definelayered and protracted programmes for stress resolution that encompass extensive changes acrossthe transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibitioninvolved protracted and dynamic changes of glucose and lipid metabolism and suppression ofmitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insultsthan acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellularresponse to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptomeanalysis pipeline, we further show that GCN2 is also a stress-independent bona fide target intranscriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus,identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumour cellsmay reveal new therapeutic targets and routes for cancer therapy optimisation.
Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Caputo VS, Trasanidis N, Xiao X, et al., 2021, Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro, iScience, Vol: 24, Pages: 1-31, ISSN: 2589-0042
Osteoclast development in response to RANKL is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early osteoclast development entails regulation of two alternative cell fate transcriptional programmes, osteoclast vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates osteoclast development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation.
Grosicki S, Simonova M, Spicka I, et al., 2020, Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial, The Lancet, Vol: 396, Pages: 1563-1573, ISSN: 0140-6736
Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM.Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries. Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1·3 mg/m2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562.Findings Between June 2017 and February 2019, 402 patients were randomised: 195 to SVd and 207 to Vd. Median PFS was 13·93 (95% CI 11·73–NE) with SVd versus 9·46 months (8·11–10·78) with Vd; HR 0·70, [95% CI 0·53–0·93]; P=0.0075. Most frequent grade ≥3 adverse events (SVd vs Vd) were thrombocytopenia (77 [40%] vs 35 [17%]), fatigue (26 [13%] vs 2 [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy rates (overall, 32·3% vs 47·1%; OR 0·52, [95% CI 0·35-0·79]; P=0.0010 and grade ≥2, 21&middo
Auner HW, Gavriatopoulou M, Delimpasi S, et al., 2020, Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
- Author Web Link
- Citations: 2
Mateos M, Gavriatopoulou M, Facon T, et al., 2020, Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Richard S, Chari A, Delimpasi S, et al., 2020, Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High-Risk Cytogenetic Risk Planned Subgroup Analyses from the Phase 3 Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
- Author Web Link
- Citations: 1
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