Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib.


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Type
Article
Change log
Authors
Prokoph, Nina 
Matthews, Jamie D 
Trigg, Ricky M 
Montes-Mojarro, Ivonne A 
Abstract

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

Description
Keywords
ALCL, PDX, brigatinib, crizotinib, tyrosine kinase inhibitors
Journal Title
Br J Haematol
Conference Name
Journal ISSN
0007-1048
1365-2141
Volume Title
Publisher
Wiley
Sponsorship
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675712)
Cancer Research UK (A25117)
National Institute for Health and Care Research (IS-BRC-1215-20014)
This work was supported by the Cancer Research UK Cambridge Centre [C9685/A25117]. N.P., I.A.M.M, L.K. and S.D.T were supported by a European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Network Grant, Grant No.: 675712; J.D.M. by the Alex Hulme Foundation; S.D.T by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU; L.K. was supported by the COMET Competence Center CBmed - Center for Biomarker Research in Medicine (n. FA791A0906.FFG), and the module project microOne as well as the Christian-Doppler Lab for Applied Metabolomics, and by the Austrian Science Fund (grants FWF: P26011, P29251, and P 34781); the MAPPYACTS trial by the Institut National du Cancer grant PHRC-K14–175, the Foundation ARC grant MAPY201501241, and the Association Imagine for Margo; MAPPYACTS PDX development by Fédération Enfants Cancers et Santé, Société Française de lutte contre les Cancers et les leucémies de l’Enfant et l’adolescent (SFCE), Association AREMIG and Thibault BRIET; Parrainage médecin-chercheur of Gustave Roussy. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.