Imperial College London

ProfessorHolgerAuner

Faculty of MedicineDepartment of Immunology and Inflammation

Visiting Professor
 
 
 
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Contact

 

holger.auner04 Website

 
 
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Assistant

 

Miss Mandy Sale +44 (0)20 3313 4017

 
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Location

 

4N7ACommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

152 results found

Spertini C, Bénéchet AP, Birch F, Bellotti A, Román-Trufero M, Arber C, Auner HW, Mitchell RA, Spertini O, Smirnova Tet al., 2024, Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia., Cell Death Discov, Vol: 10, ISSN: 2058-7716

The malignant microenvironment plays a major role in the development of resistance to therapies and the occurrence of relapses in acute myeloid leukemia (AML). We previously showed that interactions of AML blasts with bone marrow macrophages (MΦ) shift their polarization towards a protumoral (M2-like) phenotype, promoting drug resistance; we demonstrated that inhibiting the colony-stimulating factor-1 receptor (CSF1R) repolarizes MΦ towards an antitumoral (M1-like) phenotype and that other factors may be involved. We investigated here macrophage migration inhibitory factor (MIF) as a target in AML blast survival and protumoral interactions with MΦ. We show that pharmacologically inhibiting MIF secreted by AML blasts results in their apoptosis. However, this effect is abrogated when blasts are co-cultured in close contact with M2-like MΦ. We next demonstrate that pharmacological inhibition of MIF secreted by MΦ, in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), efficiently reprograms MΦ to an M1-like phenotype that triggers apoptosis of interacting blasts. Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163+ protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes.

Journal article

Almada LL, Barroso K, Sen S, Toruner M, Sigafoos AN, Arul GLR, Pease DR, Vera RE, Olson RLO, Auner HW, Pedeux R, Iovanna JL, Chevet E, Fernandez-Zapico MEet al., 2023, GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1, BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, Vol: 1866, ISSN: 1874-9399

Journal article

Jagannath S, Delimpasi S, Grosicki S, Auner H, Spicka I, Dimopoulos Met al., 2023, QUALITY OF LIFE IN PATIENTS WITH MULTIPLE MYELOMA TREATED WITH SELINEXOR WHO HAD DOSE REDUCTIONS: A SUBGROUP ANALYSIS OF THE BOSTON STUDY, Publisher: ONCOLOGY NURSING SOC, ISSN: 0190-535X

Conference paper

Lecat CSY, Fisher A, Atta M, Camilleri M, McCourt O, Land J, Worthington S, Hart A, Daniel A, Uddin I, Roche C, Auner HW, Yong Ket 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.

Journal article

Royle K-L, Coulson AB, Ramasamy K, Cairns DA, Hockaday A, Quezada S, Drayson M, Kaiser M, Owen R, Auner HW, Cook G, Meads D, Olivier C, Barnard L, Lambkin R, Paterson A, Dawkins B, Chapman M, Pratt G, Popat R, Jackson G, Bygrave C, Sive J, de Tute R, Chantry A, Parrish C, Cook M, Asher S, Yong Ket 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

Journal article

ElGendy K, Barwick T, Auner HW, Chaidos A, Wallitt K, Sergot A, Rockall Aet 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

Journal article

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.

Journal article

Auner HW, Brown SR, Walker K, Kendall J, Dawkins B, Meads D, Morgan GJ, Kaiser MF, Cook M, Roberts S, Parrish C, Cook Get 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

Journal article

Benjamin R, Garg M, Basu S, Chai Y, DeCastro A, Boulhabel F, Shah J, Auner Het 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) <i>Versus</i> Bortezomib and Dexamethasone (Vd): A Post Hoc Analysis from the BOSTON Trial, Publisher: WILEY, Pages: 127-128, ISSN: 0007-1048

Conference paper

Trasanidis N, Katsarou A, Ponnusamy K, Shen Y-A, Kostopoulos I, Bergonia B, Keren K, Reema P, Xiao X, Szydlo RM, Sabbattini PMR, Roberts IAG, Auner HW, Naresh KN, Chaidos A, Wang T-L, Magnani L, Caputo VS, Karadimitris Aet 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

Journal article

Delimpasi S, Mateos MV, Auner HW, Gavriatopoulou M, Dimopoulos MA, Quach H, Pylypenko H, Hajek R, Leleu X, Dolai TK, Sinha DK, Venner CP, Benjamin R, Garg MK, Doronin V, Levy Y, Moreau P, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set al., 2022, 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

Journal article

Ponnusamy K, Tzioni MM, Begum M, Robinson ME, Caputo VS, Katsarou A, Trasanidis N, Xiao X, Kostopoulos I, Iskander D, Roberts I, Trivedi P, Auner HW, Naresh K, Chaidos A, Karadimitris Aet al., 2022, The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma, HAEMATOLOGICA, Vol: 107, Pages: 721-732, ISSN: 0390-6078

Journal article

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.

Journal article

Jagannath S, Facon T, Badros AZ, Levy M, Moreau P, Delimpasi S, Simonova M, Spicka I, Kriachok I, Gavriatopoulou M, Pylypenko H, Auner HW, Leleu X, Doronin V, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Mesa MG, Jurczyszyn A, Robak T, Galli M, Wallington-Beddoe CT, Radinoff A, Salogub G, Stevens D, Basu S, Liberati AM, Quach H, Marinova VSG, Bila JS, Katodritou E, De Castro A, Chai Y, Van Domelen DR, Mishal M, Bentur OS, Shah J, Shacham S, Kauffman MG, Grosicki S, Richardson PGet 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, 63rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, Pages: 3793-+, ISSN: 0006-4971

Conference paper

Bahlis NJ, Richard S, White DJ, Grosicki S, Chen C, Delimpasi S, Sutherland HJ, Maslyak Z, Sebag M, Gavriatopoulou M, Lentzsch S, Chari A, Simonova M, Spicka I, Kriachok I, Dimopoulos MA, Pylypenko H, Auner HW, Leleu X, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens D, Quach H, Jagannath S, Moreau P, Levy M, Badros AZ, Anderson LD, Facon T, Mateos M-V, Cavo M, De Castro A, Chai Y, Van Domelen DR, Mishal M, Bentur OS, Shah J, Shacham S, Kauffman MG, Richardson PGet al., 2021, Effects of Cytogenetic Risk on Outcomes in Multiple Myeloma Treated with Selinexor, Bortezomib, and Dexamethasone (XVd), 63rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Chavda SJ, Galas-Filipowicz D, Fitzsimons E, Mikolajczak A, Tooze S, Auner HW, Simon K, Khwaja A, Yong Ket al., 2021, Autophagy Blockade Disrupts Myeloma Cell Recovery from Proteasome Inhibition and Enhances Apoptosis, 63rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971

Conference paper

Sanchez L, Leleu X, Beaumont JL, Yu H, Hudgens S, Simonova M, Auner HW, Quach H, Delimpasi S, Špička I, Pour L, Kriachok I, Dimopoulos MA, Usenko G, Hájek R, Benjamin R, Sinha DK, Venner C, Illmer T, Garg MK, Stevens DA, Jagannath S, Levy M, Anderson LD, Bahlis NJ, Facon T, Cavo M, Chai Y, Ma X, Tang S, Leong H, Shah J, Shacham S, Kauffman M, Richardson P, Grosicki Set 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

Journal article

Yong KL, Hinsley S, Auner HW, Bygrave C, Kaiser MF, Ramasamy K, De Tute RM, Sherratt D, Flanagan L, Garg M, Hawkins S, Williams C, Cavenagh J, Rabin NK, Croft J, Morgan G, Davies F, Owen RG, Brown SRet 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.

Journal article

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.

Journal article

Richard S, Chari A, Delimpasi S, Simonova M, Spicka I, Pour L, Kriachok I, Dimopoulos MA, Pylypenko H, Auner HW, Leleu X, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros A, Anderson LD, Bahlis NJ, Facon T, Mateos MV, Cavo M, Chang H, Landesman Y, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Grosicki S, Richardson PGet 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

Journal article

Mateos MV, Gavriatopoulou M, Facon T, Auner HW, Leleu X, Hajek R, Dimopoulos MA, Delimpasi S, Simonova M, Spicka I, Pour L, Kriachok I, Pylypenko H, Doronin V, Usenko G, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros AZ, Anderson LD, Bahlis NJ, Cavo M, Chai Y, Jeha J, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set 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.

Journal article

Auner HW, Gavriatopoulou M, Delimpasi S, Simonova M, Spicka I, Pour L, Dimopoulos MA, Kriachok I, Pylypenko H, Leleu X, Doronin V, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy M, Badros A, Anderson LD, Bahlis NJ, Facon T, Victoria Mateos M, Cavo M, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set 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

Journal article

Leleu X, Mateos M-V, Jagannath S, Delimpasi S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Dimopoulos MA, Pylypenko H, Auner HW, Reuben B, Venner CP, Garg M, DeCastro A, Shah JJ, Grosicki S, Richardson PGet 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., Virtual Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Facon T, Auner HW, Gavriatopoulou M, Delimpasi S, Simonova M, Spicka I, Pour L, Dimopoulos MA, Kriachok I, Pylypenko H, Leleu X, Quach H, Reuben B, Dolai TK, Sinha DK, Garg M, Stevens DA, Shah JJ, Richardson PG, Grosicki Set al., 2021, Survival among older patients with previously treated multiple myeloma treated with selinexor, bortezomib, and dexamethasone (XVd) in the BOSTON study., Virtual Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Saavedra-Garcia P, Roman-Trufero M, Al-Sadah HA, Blighe K, Lopez-Jimenez E, Christoforou M, Penfold L, Capece D, Xiong X, Miao Y, Parzych K, Caputo V, Siskos AP, Encheva V, Liu Z, Thiel D, Kaiser MF, Piazza P, Chaidos A, Karadimitris A, Franzoso G, Snijder AP, Keun HC, Oyarzún DA, Barahona M, Auner Het 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.

Journal article

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar P, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gomez E, Alessandri C, Ali M, Al-Bari MAA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Alves S, da Costa CA, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Anton Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araujo WL, Araya J, Arden C, Arevalo M-A, Arguelles S, Arias E, Arikkath J, Arimoto H, Ariosa AR, Armstrong-James D, Arnaune-Pelloquin L, Aroca A, Arroyo DS, Arsov I, Artero R, Asaro DML, Aschner M, Ashrafizadeh M, Ashur-Fabian O, Atanasov AG, Au AK, Auberger P, Auner HW, Aurelian L, Autelli R, Avagliano L, Avalos Y, Aveic S, Aveleira CA, AvinWittenberg T, Aydin Y, Ayton S, Ayyadevara S, Azzopardi M, Baba M, Backer JM, Backues SK, Bae D-H, Bae O-N, Bae SH, Baehrecke EH, Baek A, Baek S-H, Baek SH, Bagetta G, Bagniewska-Zadworna A, Bai H, Bai J, Bai X, Bai Y, Bairagi N, Baksi S, Balbi T, Baldari CT, Balduini W, Ballabio A, Ballester M, Balazadeh S, Balzan R, Bandopadhyay R, Banerjee S, Banerjee S, Bao Y, Baptista MS, Baracca A, Barbati C, Bargiela A, Barila D, Barlow PG, Barmada SJ, Barreiro E, Barreto GE, Bartek J, Bartel B, Bartolome A, Barve GR, Basagoudanavar SH, Bassham DC, Jr RCB, Basu A, Batoko H, Batten I, Baulieu EE, Baumgarner BL, Bayry J, Beale R, Beau I, Beaumatin F, Bechara LRG, Beck GR, Beers MF, Begun J, Behrends C, Behrens GMN, Bei R, Bejarano E, Bel S, Behl C, Belaid A, Belgareh-Touzeet 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.

Journal article

Caputo VS, Trasanidis N, Xiao X, Robinson ME, Katsarou A, Ponnusamy K, Prinjha RK, Smithers N, Chaidos A, Auner HW, Karadimitris Aet 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.

Journal article

Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Pylypenko H, Auner H, Leleu X, Doronin V, Usenko G, Bahlis NJ, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Gironella M, Jurczyszyn A, Robak P, Galli M, Wallington-Beddoe C, Radinoff A, Salogub G, Stevens DA, Basu S, Liberati AM, Quach H, St Goranova-Marinova V, Bila J, Katodritou E, Oliynyk H, Korenkova S, Kumar J, Jagannath S, Moreau P, Levy M, White D, Gatt ME, Facon T, Mateos MV, Cavo M, Reece D, Anderson LD, Saint-Martin J-R, Jeha J, Joshi AA, Chai Y, Li L, Peddagali V, Arazy M, Shah J, Shacham S, Kauffman MG, Dimopoulos MA, Richardson PG, Delimpasi Set 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

Journal article

Auner HW, Gavriatopoulou M, Delimpasi S, Simonova M, Spicka I, Pour L, Dimopoulos MA, Kryachok I, Pylypenko H, Leleu X, Doronin VA, Usenko G, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Stevens DA, Quach H, Jagannath S, Moreau P, Levy MY, Badros AZ, Anderson LD, Bahlis NJ, Facon T, Mateos M, Cavo M, Joshi AA, Chai Y, Arazy M, Shah J, Shacham S, Kauffman MG, Richardson PG, Grosicki Set 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

Conference paper

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