Auner Lab

Auner Lab

Contact

Dr Holger Auner

  • CRUK Advanced Clinician Scientist
  • Clinical Reader in Molecular Haemato-Oncology

+44 (0)20 3313 4017
holger.auner04@imperial.ac.uk

Areas of research

Proteotoxic stress and metabolism

Myeloma cells are characterised by a unique sensitivity to inhibitors of the proteasome, which is responsible for the controlled degradation of most cellular proteins that have become damaged or are otherwise unwanted. Nevertheless, resistance to proteasome inhibitors occurs in essentially all patients to varying degrees. Accumulation of misfolded proteins in the endoplasmic reticulum (ER), which triggers proteotoxic ‘ER stress’, is widely believed to be the main mechanism of action of proteasome inhibitors. However, data from our lab and other research groups suggest complex interactions between proteasomal protein degradation and multiple metabolic processes. Our aim is to find metabolic and proteostatic vulnerabilities that we can exploit therapeutically.

Tissue biophysics in myeloma biology

Several important aspects of cancer cell biology are influenced by mechanical cues from the surrounding tissue. In particular, mechanical interactions and matrix remodelling have been shown to govern cancer cell metabolism. Tissue stiffness also impacts on normal haematopoiesis, and mechanical cues are known to modulate therapeutic responses. Moreover, we have shown that proteostasis-targeting drugs can alter tissue physical properties. We aim to understand how tissue stiffness and nutrient availability act together to rewire metabolic networks and regulate drug responses in myeloma.

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  • 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
    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

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