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.


Citation

BibTex format

@article{Yong:2021:10.3324/haematol.2021.278399,
author = {Yong, KL and Hinsley, S and Auner, HW and Bygrave, C and Kaiser, MF and Ramasamy, K and De, Tute RM and Sherratt, D and Flanagan, L and Garg, M and Hawkins, S and Williams, C and Cavenagh, J and Rabin, NK and Croft, J and Morgan, G and Davies, F and Owen, RG and Brown, SR},
doi = {10.3324/haematol.2021.278399},
journal = {Haematologica: the hematology journal},
pages = {2694--2706},
title = {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)},
url = {http://dx.doi.org/10.3324/haematol.2021.278399},
volume = {106},
year = {2021}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Yong,KL
AU - Hinsley,S
AU - Auner,HW
AU - Bygrave,C
AU - Kaiser,MF
AU - Ramasamy,K
AU - De,Tute RM
AU - Sherratt,D
AU - Flanagan,L
AU - Garg,M
AU - Hawkins,S
AU - Williams,C
AU - Cavenagh,J
AU - Rabin,NK
AU - Croft,J
AU - Morgan,G
AU - Davies,F
AU - Owen,RG
AU - Brown,SR
DO - 10.3324/haematol.2021.278399
EP - 2706
PY - 2021///
SN - 0390-6078
SP - 2694
TI - 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)
T2 - Haematologica: the hematology journal
UR - http://dx.doi.org/10.3324/haematol.2021.278399
UR - https://www.ncbi.nlm.nih.gov/pubmed/33910333
UR - https://haematologica.org/article/view/haematol.2021.278399
UR - http://hdl.handle.net/10044/1/88418
VL - 106
ER -