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{Grosicki:2020:10.1016/S0140-6736(20)32292-3,
author = {Grosicki, S and Simonova, M and Spicka, I and Pour, L and Kriachok, I and Gavriatopoulou, M and Pylypenko, H and Auner, H and Leleu, X and Doronin, V and Usenko, G and Bahlis, NJ and Hajek, R and Benjamin, R and Dolai, TK and Sinha, DK and Venner, CP and Garg, M and Gironella, M and Jurczyszyn, A and Robak, P and Galli, M and Wallington-Beddoe, C and Radinoff, A and Salogub, G and Stevens, DA and Basu, S and Liberati, AM and Quach, H and St, Goranova-Marinova V and Bila, J and Katodritou, E and Oliynyk, H and Korenkova, S and Kumar, J and Jagannath, S and Moreau, P and Levy, M and White, D and Gatt, ME and Facon, T and Mateos, MV and Cavo, M and Reece, D and Anderson, LD and Saint-Martin, J-R and Jeha, J and Joshi, AA and Chai, Y and Li, L and Peddagali, V and Arazy, M and Shah, J and Shacham, S and Kauffman, MG and Dimopoulos, MA and Richardson, PG and Delimpasi, S},
doi = {10.1016/S0140-6736(20)32292-3},
journal = {The Lancet},
pages = {1563--1573},
title = {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},
url = {http://dx.doi.org/10.1016/S0140-6736(20)32292-3},
volume = {396},
year = {2020}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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
AU - Grosicki,S
AU - Simonova,M
AU - Spicka,I
AU - Pour,L
AU - Kriachok,I
AU - Gavriatopoulou,M
AU - Pylypenko,H
AU - Auner,H
AU - Leleu,X
AU - Doronin,V
AU - Usenko,G
AU - Bahlis,NJ
AU - Hajek,R
AU - Benjamin,R
AU - Dolai,TK
AU - Sinha,DK
AU - Venner,CP
AU - Garg,M
AU - Gironella,M
AU - Jurczyszyn,A
AU - Robak,P
AU - Galli,M
AU - Wallington-Beddoe,C
AU - Radinoff,A
AU - Salogub,G
AU - Stevens,DA
AU - Basu,S
AU - Liberati,AM
AU - Quach,H
AU - St,Goranova-Marinova V
AU - Bila,J
AU - Katodritou,E
AU - Oliynyk,H
AU - Korenkova,S
AU - Kumar,J
AU - Jagannath,S
AU - Moreau,P
AU - Levy,M
AU - White,D
AU - Gatt,ME
AU - Facon,T
AU - Mateos,MV
AU - Cavo,M
AU - Reece,D
AU - Anderson,LD
AU - Saint-Martin,J-R
AU - Jeha,J
AU - Joshi,AA
AU - Chai,Y
AU - Li,L
AU - Peddagali,V
AU - Arazy,M
AU - Shah,J
AU - Shacham,S
AU - Kauffman,MG
AU - Dimopoulos,MA
AU - Richardson,PG
AU - Delimpasi,S
DO - 10.1016/S0140-6736(20)32292-3
EP - 1573
PY - 2020///
SN - 0140-6736
SP - 1563
TI - 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
T2 - The Lancet
UR - http://dx.doi.org/10.1016/S0140-6736(20)32292-3
UR - https://www.sciencedirect.com/science/article/pii/S0140673620322923?via%3Dihub
UR - http://hdl.handle.net/10044/1/82245
VL - 396
ER -

Hugh and Josseline Langmuir Myeloma Centre