Zablonski Kevin G, Skupa Sydney A, Eiken Alexandria P, Sundaram Suchitra, Mavis Cory, Gu Juan Jenny, Torka Pallawi, Ghione Paola, El-Gamal Dalia, Hernandez-Ilizaliturri Francisco J
Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Leuk Lymphoma. 2024 Dec;65(14):2129-2137. doi: 10.1080/10428194.2024.2398663. Epub 2024 Sep 27.
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. and/or 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.
慢性淋巴细胞白血病（CLL）仍然无法治愈，而且其对一线治疗产生耐药性的能力已被证明具有挑战性。溴结构域和额外末端蛋白，特别是含溴结构域蛋白4（BRD4），在CLL的基因表达中不可或缺，并提供了一个有前景的治疗靶点。在本研究中，我们研究了BRD4抑制剂OPN-51107单独以及与BCL-2抑制剂维奈克拉联合使用时，在CLL细胞系和患者来源的CLL样本中的活性。我们证明，OPN-51107在CLL细胞系和患者来源的样本中均诱导抗肿瘤活性，包括复发/难治性（R/R）样本以及具有高危特征（即 缺失和/或 缺失）的样本。重要的是，无论R/R或缺失状态如何，OPN-51107和维奈克拉的联合用药在对伊布替尼耐药的CLL细胞和患者来源的CLL样本中均表现出协同细胞毒性。本研究确立了联合使用OPN-51107和维奈克拉治疗耐药和/或高危CLL的临床前疗效，并为其作为联合疗法的进一步开发提供了支持。
