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Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

Combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Carsten U Niemann
  • Helena I Mora-Jensen
  • Eman L Dadashian
  • Fanny Krantz
  • Todd Covey
  • Shih-Ann Chen
  • Nicholas Chiorazzi
  • Raquel Izumi
  • Roger Ulrich
  • Brian J Lannutti
  • Adrian Wiestner
  • Sarah E M Herman
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Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of BTK and PI3K-delta is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3K-delta and BTK inhibitors. <p>Experimental design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3K-delta inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.</p> <p>Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. While single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over two weeks compared to either single agent. The combination reduced tumor proliferation, NF-KB signaling and expression of BCL-xL and MCL-1 more potently than single-agent therapy.</p> <p>Conclusion: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind23
Udgave nummer19
Sider (fra-til)5814-5823
ISSN1078-0432
DOI
StatusUdgivet - okt. 2017

ID: 51530692