LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia

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 l...

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Veröffentlicht in:Haematologica (Roma) 2025-01, Vol.110 (1), p.78
Hauptverfasser: Ravikrishnan, Janani, Diaz-Rohena, Daisy Y, Muhowski, Elizabeth, Mo, Xiaokui, Lai, Tzung-Huei, Misra, Shrilekha, Williams, Charmelle D, Sanchez, John, Mitchell, Andrew, Satpati, Suresh, Perry, Elizabeth, Kaufman, Tierney, Liu, Chaomei, Lozanski, Arletta, Lozanski, Gerard, Rogers, KerryA, Kittai, Adam S, Bhat, Seema A, Collins, Mary C, Davids, Matthew S, Jain, Nitin, Wierda, William G, Lapalombella, Rosa, Byrd, John C, Tan, Fenlai, Chen, Yi, Chen, Yu, Shen, Yue, Anthony, Stephen P, Woyach, Jennifer A, Sampath, Deepa
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container_issue 1
container_start_page 78
container_title Haematologica (Roma)
container_volume 110
creator Ravikrishnan, Janani
Diaz-Rohena, Daisy Y
Muhowski, Elizabeth
Mo, Xiaokui
Lai, Tzung-Huei
Misra, Shrilekha
Williams, Charmelle D
Sanchez, John
Mitchell, Andrew
Satpati, Suresh
Perry, Elizabeth
Kaufman, Tierney
Liu, Chaomei
Lozanski, Arletta
Lozanski, Gerard
Rogers, KerryA
Kittai, Adam S
Bhat, Seema A
Collins, Mary C
Davids, Matthew S
Jain, Nitin
Wierda, William G
Lapalombella, Rosa
Byrd, John C
Tan, Fenlai
Chen, Yi
Chen, Yu
Shen, Yue
Anthony, Stephen P
Woyach, Jennifer A
Sampath, Deepa
description 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.
doi_str_mv 10.3324/haematol.2023.284353
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subjects Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
bcl-X Protein - antagonists & inhibitors
bcl-X Protein - genetics
bcl-X Protein - metabolism
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Bridged Bicyclo Compounds, Heterocyclic - therapeutic use
Cell Line, Tumor
Disease Models, Animal
Drug Resistance, Neoplasm - drug effects
Humans
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - mortality
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Mice
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
Xenograft Model Antitumor Assays
title LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia
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