Faculty, Staff and Student Publications

Publication Date

1-1-2025

Journal

Haematologica

Abstract

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax-naïve and -resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax-responsive and -relapsed CLL.

Keywords

Leukemia, Lymphocytic, Chronic, B-Cell, Humans, Animals, Mice, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, bcl-X Protein, Disease Models, Animal, Xenograft Model Antitumor Assays

DOI

10.3324/haematol.2023.284353

PMID

39113656

PMCID

PMC11694131

PubMedCentral® Posted Date

8-8-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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