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Poster 2167: DLBCL PDX Models with Diverse Genotypes for BTKi Testing

Efficacy Assessment of the BTK Inhibitor Ibrutinib in De Novo and Viral-Induced B Cell Lymphoma

Jessie J Wang, Meiling Zheng, Chunjuan Huang, Xuesong Huang, Yanrui Song, Wubin Qian, Likun Zhang, Jie Cai, Sheng Guo, Henry Q. X. Li, Davy X. Ouyang
CrownBio 2018. Poster 2167: DLBCL PDX Models with Diverse Genotypes for BTKi Testing
Bruton's tyrosine kinase (BTK) activation is a major oncogenic driver for various B cell-derived lymphoid cancers. The BTK inhibitor ibrutinib has been approved for a range of malignancies (e.g. mantle cell lymphoma, chronic lymphocytic leukemia), and has also shown encouraging efficacy in the ABC subtype, but not GCB subtype, of DLBCL.

To allow further testing of ibrutinib in vivo for DLBCL, clinically relevant preclinical models are needed which recapitulate the diverse genotypes of de novo DLBCL patients, covering the different subtypes and single/double gene mutations. CrownBio has therefore established a series of patient-derived xenograft (PDX) DLBCL models, including wild type PDX, the MYD88L265P single mutant model, and two MYD88L265P/CD79BY197N double mutant PDX.

These models have been tested with ibrutinib (with continuous administration of a low dose through drinking water trialed), alongside a cohort of EBV-transformed B lymphoma PDX, which share similar histopathology with de novo DLBCL, but have distinct molecular pathology signatures and different pathogenesis.

Read this Poster to Discover:

  • That, in de novo DLBCL PDX models, CD79B activating mutation is a predictive biomarker for chronic activation of BCR signaling, and a generally good response to BTK inhibitors; however for CD79B wild type PDX models (even those with MYD88 activating mutation) tumorigenicity can be partially dependent on BCR signaling
  • That EBV+ B lymphoma models are resistant to ibrutinib, and that the pathogenesis of EBV+ B lymphoma is likely to be associated with other immune deficiencies, such as interferon signaling, but not BCR
  • That DLBCL and EBV-induced lymphoma PDX models provide a valuable preclinical platform for evaluating BTK inhibitors, as well as future drug discovery efforts on other targets in the BCR and MYD88 pathways, such as PI3K, SYK, and IRAK4

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