Kevin G Zablonski, Sydney A Skupa, Alexandria P Eiken, Suchitra Sundaram, Cory Mavis, Juan Jenny Gu, Pallawi Torka, Paola Ghione, Dalia El-Gamal, Francisco J Hernandez-Ilizaliturri
{"title":"用 OPN-51107 靶向抑制 BET 与 venetoclax 协同治疗慢性淋巴细胞白血病。","authors":"Kevin G Zablonski, Sydney A Skupa, Alexandria P Eiken, Suchitra Sundaram, Cory Mavis, Juan Jenny Gu, Pallawi Torka, Paola Ghione, Dalia El-Gamal, Francisco J Hernandez-Ilizaliturri","doi":"10.1080/10428194.2024.2398663","DOIUrl":null,"url":null,"abstract":"<p><p>Chronic lymphocytic leukemia (CLL) remains incurable and its ability to acquire resistance to front-line therapeutics has proved challenging. Bromodomain and extra-terminal proteins, particularly bromodomain-containing protein 4 (BRD4), are integral to gene expression in CLL and offer a promising therapeutic target. In this study, we examined the activity of the BRD4 inhibitor OPN-51107 alone and in combination with the BCL-2 inhibitor, venetoclax, in CLL cell lines and patient-derived CLL samples. We demonstrate that OPN-51107 induces anti-tumor activity in both CLL cell lines and patient-derived samples, including relapsed/refractory (R/R) samples and those with high-risk features (i.e. <i>ATM</i> and/or <i>TP53</i> deletions). Importantly, the combination of OPN-51107 and venetoclax exhibited synergistic cytotoxicity in ibrutinib-resistant CLL cells and patient-derived CLL samples regardless of R/R or deletion status. This study establishes the preclinical efficacy of using OPN-51107 and venetoclax in combination in therapy-resistant and/or high-risk CLL, lending support for its further development as a combination therapy.</p>","PeriodicalId":18047,"journal":{"name":"Leukemia & Lymphoma","volume":" ","pages":"2129-2137"},"PeriodicalIF":2.2000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted BET inhibition with OPN-51107 synergizes with venetoclax in chronic lymphocytic leukemia.\",\"authors\":\"Kevin G Zablonski, Sydney A Skupa, Alexandria P Eiken, Suchitra Sundaram, Cory Mavis, Juan Jenny Gu, Pallawi Torka, Paola Ghione, Dalia El-Gamal, Francisco J Hernandez-Ilizaliturri\",\"doi\":\"10.1080/10428194.2024.2398663\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Chronic lymphocytic leukemia (CLL) remains incurable and its ability to acquire resistance to front-line therapeutics has proved challenging. Bromodomain and extra-terminal proteins, particularly bromodomain-containing protein 4 (BRD4), are integral to gene expression in CLL and offer a promising therapeutic target. In this study, we examined the activity of the BRD4 inhibitor OPN-51107 alone and in combination with the BCL-2 inhibitor, venetoclax, in CLL cell lines and patient-derived CLL samples. We demonstrate that OPN-51107 induces anti-tumor activity in both CLL cell lines and patient-derived samples, including relapsed/refractory (R/R) samples and those with high-risk features (i.e. <i>ATM</i> and/or <i>TP53</i> deletions). Importantly, the combination of OPN-51107 and venetoclax exhibited synergistic cytotoxicity in ibrutinib-resistant CLL cells and patient-derived CLL samples regardless of R/R or deletion status. This study establishes the preclinical efficacy of using OPN-51107 and venetoclax in combination in therapy-resistant and/or high-risk CLL, lending support for its further development as a combination therapy.</p>\",\"PeriodicalId\":18047,\"journal\":{\"name\":\"Leukemia & Lymphoma\",\"volume\":\" \",\"pages\":\"2129-2137\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia & Lymphoma\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/10428194.2024.2398663\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia & Lymphoma","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/10428194.2024.2398663","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/27 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Targeted BET inhibition with OPN-51107 synergizes with venetoclax in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) remains incurable and its ability to acquire resistance to front-line therapeutics has proved challenging. Bromodomain and extra-terminal proteins, particularly bromodomain-containing protein 4 (BRD4), are integral to gene expression in CLL and offer a promising therapeutic target. In this study, we examined the activity of the BRD4 inhibitor OPN-51107 alone and in combination with the BCL-2 inhibitor, venetoclax, in CLL cell lines and patient-derived CLL samples. We demonstrate that OPN-51107 induces anti-tumor activity in both CLL cell lines and patient-derived samples, including relapsed/refractory (R/R) samples and those with high-risk features (i.e. ATM and/or TP53 deletions). Importantly, the combination of OPN-51107 and venetoclax exhibited synergistic cytotoxicity in ibrutinib-resistant CLL cells and patient-derived CLL samples regardless of R/R or deletion status. This study establishes the preclinical efficacy of using OPN-51107 and venetoclax in combination in therapy-resistant and/or high-risk CLL, lending support for its further development as a combination therapy.
期刊介绍:
Leukemia & Lymphoma in its fourth decade continues to provide an international forum for publication of high quality clinical, translational, and basic science research, and original observations relating to all aspects of hematological malignancies. The scope ranges from clinical and clinico-pathological investigations to fundamental research in disease biology, mechanisms of action of novel agents, development of combination chemotherapy, pharmacology and pharmacogenomics as well as ethics and epidemiology. Submissions of unique clinical observations or confirmatory studies are considered and published as Letters to the Editor