Auner Lab

Contact


Dr Holger Auner

  • Clinical Senior Lecturer and Honorary Consultant in Haematology
  • Head of Translational Research at the Centre
  • Group Leader - Cancer Cell Protein Metabolism

+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
    Saavedra-Garcia P, Martini F, Auner HW, 2020,

    Proteasome inhibition in multiple myeloma: lessons for other cancers

    , AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, Vol: 318, Pages: C451-C462, ISSN: 0363-6143
  • Journal article
    Morris C, Chabannon C, Masszi T, Russell N, Nahi H, Kobbe G, Krejci M, Auner H, Pohlreich D, Hayden P, Basak GW, Lenhoff S, Schaap N, van Biezen A, Knol C, Iacobelli S, Liu Q, Celanovic M, Garderet L, Kröger Net al., 2020,

    Results from a multi-center, non-interventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor

    , Bone Marrow Transplantation, Vol: 55, Pages: 356-366, ISSN: 1476-5365

    Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of haematopoietic stem cells (HSCs) for collection and subsequent autologous haematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM).This international, multicenter, non-interventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF+plerixafor (G-CSF+P) versus G-CSF-; G-CSF+P versus G-CSF+chemotherapy (G-CSF+C); and G-CSF+P+C versus G-CSF+C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF+P versus G-CSF cohorts, 129 versus 129 in the G-CSF+P versus G-CSF+C cohort and 117 versus 117 in the G-CSF+P+C versus G-CSF+C cohort, were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded pre-specified boundaries; non-inferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF+P remains an option for the mobilization of HSCs in poor-mobilizers with MM with no substantial differences in PFS, OS and CIR in comparison with other regimens.

  • Journal article
    Graziani G, Herget G, Ihorst G, Zeissig M, Chaidos A, Auner H, Duyster J, Waesch R, Engelhardt Met al., 2020,

    Time from first symptom onset to the final diagnosis of Multiple Myeloma (MM) - possible risks and future solutions: retrospective and prospective ‘Deutsche Studiengruppe MM’ (DSMM) and ‘European Myeloma Network’ (EMN) analysis

    , Leukemia and Lymphoma, Vol: 61, Pages: 875-886, ISSN: 1026-8022

    Multiple Myeloma (MM) often presents with unspecific symptoms and is challenging to diagnose. We performed this DSMM/EMN-analysis via test-(retro-) and validation (prospective) study to determine the time interval from the onset of first symptoms to the diagnosis of MM. The retrospective and prospective analyses were performed in 101 and 176 patients, respectively. The median time from first symptoms to the MM diagnosis in both cohorts was 4 and 6 months, respectively. Frequencies of MM-related pathologic bone fractures, renal and infectious complications at diagnosis occurred in 41%, 35% and 16% of patients, respectively. Our MM-questionnaire determined that 39% of patients were dissatisfied with the diagnostic process. PFS and OS proved insignificantly different with shorter (≤6) and longer (>6 months) latency periods. In conclusion, our in depth studies demonstrate that delays in diagnosis do not decrease PFS or OS, but induce MM-related complications and influence patients' satisfaction with their medical care.

  • Journal article
    Bringhen S, Milan A, D'Agostino M, Ferri C, Wäsch R, Gay F, Larocca A, Offidani M, Zweegman S, Terpos E, Goldschmidt H, Cavo M, Ludwig H, Driessen C, Auner H, Caers J, Gramatzki M, Dimopoulos MA, Boccadoro M, Einsele H, Sonneveld P, Engelhardt Met al., 2019,

    Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib - A Consensus Paper by the European Myeloma Network and the Italian Society of Arterial Hypertension

    , Journal of Internal Medicine, Vol: 286, Pages: 63-74, ISSN: 0954-6820

    The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies in relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome, the risk-benefit ratio of diagnostic and therapeutic tools and thereby to achieve myeloma response with novel combination approaches, while preventing CVAEs. Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions. This article is protected by copyright. All rights reserved.

  • Journal article
    Tornatore L, Capece D, D'Andrea D, Begalli F, Verzella D, Bennett J, Acton G, Campbell EA, Kelly J, Tarbit M, Adams N, Bannoo S, Leonardi A, Sandomenico A, Raimondo D, Ruvo M, Chambery A, Oblak M, Al-Obaidi MJ, Kaczmarski RS, Gabriel I, Oakervee HE, Kaiser MF, Wechalekar A, Benjamin R, Apperley JF, Auner HW, Franzoso Get al., 2019,

    Clinical proof of concept for a safe and effective NF-κB-targeting strategy in multiple myeloma

    , British Journal of Haematology, Vol: 185, Pages: 588-592, ISSN: 1365-2141

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