Patel V M, Balakrishnan K, Douglas M, Tibbitts T, Xu E Y, Kutok J L, Ayers M, Sarkar A, Guerrieri R, Wierda W G, O'Brien S, Jain N, Stern H M, Gandhi V
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
Leukemia. 2017 Sep;31(9):1872-1881. doi: 10.1038/leu.2016.382. Epub 2016 Dec 26.
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.
度维利塞是一种口服的PI3K-δ和PI3K-γ双重抑制剂，正在进行治疗慢性淋巴细胞白血病（CLL）和惰性非霍奇金淋巴瘤的III期试验。在CLL中，度维利塞单药治疗与较高的国际慢性淋巴细胞白血病研讨会（iwCLL）和淋巴结反应率相关，但完全缓解很少见。为了表征度维利塞的分子效应，我们从参与度维利塞I期试验的CLL患者中获取了样本。基因表达研究（RNA测序、Nanostring、Affymetrix芯片和实时逆转录PCR）表明BCL2以及几个仅含BH3结构域的促凋亡基因的表达增加。与转录水平的诱导相一致，反相蛋白质阵列和免疫印迹证实了蛋白质水平的增加。与来自同一患者的治疗前CLL细胞相比，BCL2抑制剂维奈托克在体外培养的来自度维利塞治疗患者的CLL细胞中诱导了更大程度的细胞凋亡。即使在模拟肿瘤微环境的条件下培养的CLL细胞中，度维利塞和维奈托克的体外联合使用也导致细胞凋亡增强。这些数据为在临床上测试度维利塞和维奈托克的联合使用提供了机制依据。正在对包括CLL在内的B细胞恶性肿瘤患者评估这种联合治疗方案（NCT02640833）。
