• Je něco špatně v tomto záznamu ?

Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma

BS. Willis, K. Mongeon, H. Dry, IL. Neveras, N. Bryan, M. Pandya, J. Roderick-Richardson, W. Xu, L. Yang, A. Rosen, C. Reimer, L. Tuskova, P. Klener, JT. Mettetal, G. Lenz, ST. Barry

. 2024 ; 38 (12) : 2663-2674. [pub] 20240916

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003266
E-zdroje Online Plný text

NLK ProQuest Central od 2000-01-01 do Před 1 rokem
Open Access Digital Library od 1997-01-01
Nursing & Allied Health Database (ProQuest) od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy

PubMed 39284898
DOI 10.1038/s41375-024-02401-9
Knihovny.cz E-zdroje

The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc25003266
003      
CZ-PrNML
005      
20250206104217.0
007      
ta
008      
250121s2024 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1038/s41375-024-02401-9 $2 doi
035    __
$a (PubMed)39284898
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Willis, Brandon S $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
245    10
$a Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma / $c BS. Willis, K. Mongeon, H. Dry, IL. Neveras, N. Bryan, M. Pandya, J. Roderick-Richardson, W. Xu, L. Yang, A. Rosen, C. Reimer, L. Tuskova, P. Klener, JT. Mettetal, G. Lenz, ST. Barry
520    9_
$a The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
650    12
$a difúzní velkobuněčný B-lymfom $x farmakoterapie $x patologie $7 D016403
650    _2
$a lidé $7 D006801
650    12
$a sulfonamidy $x farmakologie $x terapeutické užití $7 D013449
650    12
$a bicyklické sloučeniny heterocyklické $x farmakologie $x terapeutické užití $7 D019086
650    _2
$a zvířata $7 D000818
650    _2
$a myši $7 D051379
650    12
$a protoonkogenní proteiny c-akt $x metabolismus $7 D051057
650    12
$a protoonkogenní proteiny c-bcl-2 $x antagonisté a inhibitory $x metabolismus $7 D019253
650    12
$a protokoly antitumorózní kombinované chemoterapie $x farmakologie $x terapeutické užití $7 D000971
650    12
$a pyrimidiny $x farmakologie $x terapeutické užití $7 D011743
650    12
$a xenogenní modely - testy antitumorózní aktivity $7 D023041
650    _2
$a pyrroly $x farmakologie $x terapeutické užití $7 D011758
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a apoptóza $x účinky léků $7 D017209
650    _2
$a proliferace buněk $x účinky léků $7 D049109
650    _2
$a rituximab $x farmakologie $x terapeutické užití $7 D000069283
650    _2
$a myši SCID $7 D016513
650    _2
$a fosfohydroláza PTEN $x metabolismus $7 D051059
655    _2
$a časopisecké články $7 D016428
700    1_
$a Mongeon, Kevin $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Dry, Hannah $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Neveras, India L $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Bryan, Nadezda $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Pandya, Meghana $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Roderick-Richardson, Justine $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Xu, Wendan $u Department of Medicine A, Haematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
700    1_
$a Yang, Li $u Department of Medicine A, Haematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
700    1_
$a Rosen, Alan $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Reimer, Corinne $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Tuskova, Liliana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
700    1_
$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
700    1_
$a Mettetal, Jerome T $u Bioscience, Early Oncology, AstraZeneca, Boston, USA
700    1_
$a Lenz, Georg $u Department of Medicine A, Haematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany $1 https://orcid.org/0000000247281693
700    1_
$a Barry, Simon T $u Bioscience, Early Oncology, AstraZeneca, Cambridge, UK. simon.t.barry@astrazeneca.com $1 https://orcid.org/0000000285110588
773    0_
$w MED00003138 $t Leukemia $x 1476-5551 $g Roč. 38, č. 12 (2024), s. 2663-2674
856    41
$u https://pubmed.ncbi.nlm.nih.gov/39284898 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20250121 $b ABA008
991    __
$a 20250206104213 $b ABA008
999    __
$a ok $b bmc $g 2263175 $s 1239273
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 38 $c 12 $d 2663-2674 $e 20240916 $i 1476-5551 $m Leukemia $n Leukemia $x MED00003138
LZP    __
$a Pubmed-20250121

Najít záznam

Citační ukazatele

Možnosti archivace