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...
Gespeichert in:
Veröffentlicht in: | Haematologica (Roma) 2025-01, Vol.110 (1), p.78 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | |
---|---|
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 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_3090635640</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3090635640</sourcerecordid><originalsourceid>FETCH-LOGICAL-p566-7c3012b7249483e07afdb4cc1f06d3ab58e51f66609ab96a01e116a3b871d7733</originalsourceid><addsrcrecordid>eNpNkMtOwzAQRS0EoqXwBwh5ySatH4mTLKHiJVWCRffVxJkQgx2X2Kna_-CDaUWRWN0j3aMZzRByzdlUSpHOWkAH0dupYEJORZHKTJ6QMc9KkRS54Kf_eEQuQvhgTLCyzM_JSJacS5WpMflevCWcF9QECrTzG7T0PtFoLbU7t269AyrojOI29pBY6N-Rmq41lYm-p7GFSGt0vgv7OmKg2DRGg97tJep8jTZQ39ANdhi9trDtMZgQoYtUt73vjD6u0bt4YBw-0Rm4JGcN2IBXx5yQ5ePDcv6cLF6fXuZ3i2SdKZXkWjIuqlykZVpIZDk0dZVqzRumaglVVmDGG6UUK6EqFTCOnCuQVZHzOs-lnJDb37Hr3n8NGOLKmXC4HTr0Q1hJVjIlM5WyvXpzVIfKYb1a98ZBv1v9PVL-AFaIeNo</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3090635640</pqid></control><display><type>article</type><title>LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central</source><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</creator><creatorcontrib>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</creatorcontrib><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.</description><identifier>ISSN: 1592-8721</identifier><identifier>EISSN: 1592-8721</identifier><identifier>DOI: 10.3324/haematol.2023.284353</identifier><identifier>PMID: 39113656</identifier><language>eng</language><publisher>Italy</publisher><subject>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</subject><ispartof>Haematologica (Roma), 2025-01, Vol.110 (1), p.78</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,861,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39113656$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ravikrishnan, Janani</creatorcontrib><creatorcontrib>Diaz-Rohena, Daisy Y</creatorcontrib><creatorcontrib>Muhowski, Elizabeth</creatorcontrib><creatorcontrib>Mo, Xiaokui</creatorcontrib><creatorcontrib>Lai, Tzung-Huei</creatorcontrib><creatorcontrib>Misra, Shrilekha</creatorcontrib><creatorcontrib>Williams, Charmelle D</creatorcontrib><creatorcontrib>Sanchez, John</creatorcontrib><creatorcontrib>Mitchell, Andrew</creatorcontrib><creatorcontrib>Satpati, Suresh</creatorcontrib><creatorcontrib>Perry, Elizabeth</creatorcontrib><creatorcontrib>Kaufman, Tierney</creatorcontrib><creatorcontrib>Liu, Chaomei</creatorcontrib><creatorcontrib>Lozanski, Arletta</creatorcontrib><creatorcontrib>Lozanski, Gerard</creatorcontrib><creatorcontrib>Rogers, KerryA</creatorcontrib><creatorcontrib>Kittai, Adam S</creatorcontrib><creatorcontrib>Bhat, Seema A</creatorcontrib><creatorcontrib>Collins, Mary C</creatorcontrib><creatorcontrib>Davids, Matthew S</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Wierda, William G</creatorcontrib><creatorcontrib>Lapalombella, Rosa</creatorcontrib><creatorcontrib>Byrd, John C</creatorcontrib><creatorcontrib>Tan, Fenlai</creatorcontrib><creatorcontrib>Chen, Yi</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Shen, Yue</creatorcontrib><creatorcontrib>Anthony, Stephen P</creatorcontrib><creatorcontrib>Woyach, Jennifer A</creatorcontrib><creatorcontrib>Sampath, Deepa</creatorcontrib><title>LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia</title><title>Haematologica (Roma)</title><addtitle>Haematologica</addtitle><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.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>bcl-X Protein - antagonists & inhibitors</subject><subject>bcl-X Protein - genetics</subject><subject>bcl-X Protein - metabolism</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Humans</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Mice</subject><subject>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Sulfonamides - pharmacology</subject><subject>Sulfonamides - therapeutic use</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1592-8721</issn><issn>1592-8721</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkMtOwzAQRS0EoqXwBwh5ySatH4mTLKHiJVWCRffVxJkQgx2X2Kna_-CDaUWRWN0j3aMZzRByzdlUSpHOWkAH0dupYEJORZHKTJ6QMc9KkRS54Kf_eEQuQvhgTLCyzM_JSJacS5WpMflevCWcF9QECrTzG7T0PtFoLbU7t269AyrojOI29pBY6N-Rmq41lYm-p7GFSGt0vgv7OmKg2DRGg97tJep8jTZQ39ANdhi9trDtMZgQoYtUt73vjD6u0bt4YBw-0Rm4JGcN2IBXx5yQ5ePDcv6cLF6fXuZ3i2SdKZXkWjIuqlykZVpIZDk0dZVqzRumaglVVmDGG6UUK6EqFTCOnCuQVZHzOs-lnJDb37Hr3n8NGOLKmXC4HTr0Q1hJVjIlM5WyvXpzVIfKYb1a98ZBv1v9PVL-AFaIeNo</recordid><startdate>20250101</startdate><enddate>20250101</enddate><creator>Ravikrishnan, Janani</creator><creator>Diaz-Rohena, Daisy Y</creator><creator>Muhowski, Elizabeth</creator><creator>Mo, Xiaokui</creator><creator>Lai, Tzung-Huei</creator><creator>Misra, Shrilekha</creator><creator>Williams, Charmelle D</creator><creator>Sanchez, John</creator><creator>Mitchell, Andrew</creator><creator>Satpati, Suresh</creator><creator>Perry, Elizabeth</creator><creator>Kaufman, Tierney</creator><creator>Liu, Chaomei</creator><creator>Lozanski, Arletta</creator><creator>Lozanski, Gerard</creator><creator>Rogers, KerryA</creator><creator>Kittai, Adam S</creator><creator>Bhat, Seema A</creator><creator>Collins, Mary C</creator><creator>Davids, Matthew S</creator><creator>Jain, Nitin</creator><creator>Wierda, William G</creator><creator>Lapalombella, Rosa</creator><creator>Byrd, John C</creator><creator>Tan, Fenlai</creator><creator>Chen, Yi</creator><creator>Chen, Yu</creator><creator>Shen, Yue</creator><creator>Anthony, Stephen P</creator><creator>Woyach, Jennifer A</creator><creator>Sampath, Deepa</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20250101</creationdate><title>LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p566-7c3012b7249483e07afdb4cc1f06d3ab58e51f66609ab96a01e116a3b871d7733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>bcl-X Protein - antagonists & inhibitors</topic><topic>bcl-X Protein - genetics</topic><topic>bcl-X Protein - metabolism</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Humans</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</topic><topic>Mice</topic><topic>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Sulfonamides - pharmacology</topic><topic>Sulfonamides - therapeutic use</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ravikrishnan, Janani</creatorcontrib><creatorcontrib>Diaz-Rohena, Daisy Y</creatorcontrib><creatorcontrib>Muhowski, Elizabeth</creatorcontrib><creatorcontrib>Mo, Xiaokui</creatorcontrib><creatorcontrib>Lai, Tzung-Huei</creatorcontrib><creatorcontrib>Misra, Shrilekha</creatorcontrib><creatorcontrib>Williams, Charmelle D</creatorcontrib><creatorcontrib>Sanchez, John</creatorcontrib><creatorcontrib>Mitchell, Andrew</creatorcontrib><creatorcontrib>Satpati, Suresh</creatorcontrib><creatorcontrib>Perry, Elizabeth</creatorcontrib><creatorcontrib>Kaufman, Tierney</creatorcontrib><creatorcontrib>Liu, Chaomei</creatorcontrib><creatorcontrib>Lozanski, Arletta</creatorcontrib><creatorcontrib>Lozanski, Gerard</creatorcontrib><creatorcontrib>Rogers, KerryA</creatorcontrib><creatorcontrib>Kittai, Adam S</creatorcontrib><creatorcontrib>Bhat, Seema A</creatorcontrib><creatorcontrib>Collins, Mary C</creatorcontrib><creatorcontrib>Davids, Matthew S</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Wierda, William G</creatorcontrib><creatorcontrib>Lapalombella, Rosa</creatorcontrib><creatorcontrib>Byrd, John C</creatorcontrib><creatorcontrib>Tan, Fenlai</creatorcontrib><creatorcontrib>Chen, Yi</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Shen, Yue</creatorcontrib><creatorcontrib>Anthony, Stephen P</creatorcontrib><creatorcontrib>Woyach, Jennifer A</creatorcontrib><creatorcontrib>Sampath, Deepa</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Haematologica (Roma)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ravikrishnan, Janani</au><au>Diaz-Rohena, Daisy Y</au><au>Muhowski, Elizabeth</au><au>Mo, Xiaokui</au><au>Lai, Tzung-Huei</au><au>Misra, Shrilekha</au><au>Williams, Charmelle D</au><au>Sanchez, John</au><au>Mitchell, Andrew</au><au>Satpati, Suresh</au><au>Perry, Elizabeth</au><au>Kaufman, Tierney</au><au>Liu, Chaomei</au><au>Lozanski, Arletta</au><au>Lozanski, Gerard</au><au>Rogers, KerryA</au><au>Kittai, Adam S</au><au>Bhat, Seema A</au><au>Collins, Mary C</au><au>Davids, Matthew S</au><au>Jain, Nitin</au><au>Wierda, William G</au><au>Lapalombella, Rosa</au><au>Byrd, John C</au><au>Tan, Fenlai</au><au>Chen, Yi</au><au>Chen, Yu</au><au>Shen, Yue</au><au>Anthony, Stephen P</au><au>Woyach, Jennifer A</au><au>Sampath, Deepa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia</atitle><jtitle>Haematologica (Roma)</jtitle><addtitle>Haematologica</addtitle><date>2025-01-01</date><risdate>2025</risdate><volume>110</volume><issue>1</issue><spage>78</spage><pages>78-</pages><issn>1592-8721</issn><eissn>1592-8721</eissn><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.</abstract><cop>Italy</cop><pmid>39113656</pmid><doi>10.3324/haematol.2023.284353</doi></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1592-8721 |
ispartof | Haematologica (Roma), 2025-01, Vol.110 (1), p.78 |
issn | 1592-8721 1592-8721 |
language | eng |
recordid | cdi_proquest_miscellaneous_3090635640 |
source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T01%3A19%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=LP-118%20is%20a%20novel%20B-cell%20lymphoma%202%20/%20extra-large%20inhibitor%20that%20demonstrates%20efficacy%20in%20models%20of%20venetoclaxresistant%20chronic%20lymphocytic%20leukemia&rft.jtitle=Haematologica%20(Roma)&rft.au=Ravikrishnan,%20Janani&rft.date=2025-01-01&rft.volume=110&rft.issue=1&rft.spage=78&rft.pages=78-&rft.issn=1592-8721&rft.eissn=1592-8721&rft_id=info:doi/10.3324/haematol.2023.284353&rft_dat=%3Cproquest_pubme%3E3090635640%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3090635640&rft_id=info:pmid/39113656&rfr_iscdi=true |