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
Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH.
Division of Hematopoietic Biology and Malignancy, MD Anderson Cancer Center, Houston TX.
Haematologica. 2025 Jan 1;110(1):78-91. doi: 10.3324/haematol.2023.284353.
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.
慢性淋巴细胞白血病（CLL）患者对B细胞淋巴瘤2（BCL2）抑制剂维奈托克的初始治疗反应良好。复发后，他们通常对BCL2靶向治疗仍保持敏感，但反应的持久性仍是一个问题。我们假设同时靶向BCL2和B细胞淋巴瘤-超大（BCLXL）将是治疗CLL的成功策略，包括对维奈托克复发的患者。为了验证这一假设，我们对LP-118进行了临床前研究，LP-118是一种高效的BCL2抑制剂，对BCLXL的抑制作用适中，可将血小板毒性降至最低。这项研究表明，LP-118在未使用过维奈托克和对维奈托克耐药的CLL细胞中均能有效诱导BAK激活、细胞色素C释放和细胞凋亡。值得注意的是，LP-118在表达BCL2 G101V突变的细胞系以及表达BCLXL但不依赖BCL2的细胞中均有效。使用具有免疫活性的小鼠模型Eμ-TCL1，LP-118显示出低血小板毒性，而这一毒性曾阻碍了早期的BCLXL抑制剂。最后，在RS4;11和OSU-CLL异种移植模型中，LP-118分别导致肿瘤负担减轻和生存优势。这些结果为评估LP-118治疗对维奈托克有反应和复发的CLL提供了机制依据。
