Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Leuk Lymphoma. 2013 Aug;54(8):1823-5. doi: 10.3109/10428194.2013.796051. Epub 2013 May 29.
Despite recent advances in the treatment of chronic lymphocytic leukemia (CLL) with chemoimmunotherapy, many patients with CLL are older or frail and cannot tolerate aggressive chemotherapy. Even those who can inevitably develop resistance due to factors such as deletion of pro-apoptotic factors like TP53 or the support of pro-survival signals from the stromal microenvironment. Using BH3 profiling, we found that CLL cells co-cultured with stroma are less primed to undergo apoptosis in response to BCL-2 inhibition. Currently, several approaches to BCL-2 inhibition with well-tolerated oral agents are in development in the clinic. Dosing of navitoclax (ABT-263) was complicated by thrombocytopenia due to BCL-XL inhibition, but the BCL-2 specific inhibitor ABT-199 (GDC-0199) should avoid this issue, and may overcome stroma-mediated resistance to apoptosis. We are developing BH3 profiling as a biomarker to predict response to novel therapies such as ABT-199, and to identify resistance mechanisms to new agents being studied in CLL.
尽管最近在采用化疗免疫疗法治疗慢性淋巴细胞白血病（CLL）方面取得了进展，但许多 CLL 患者年龄较大或身体虚弱，无法耐受强化化疗。即使是那些能够耐受化疗的患者，也会由于 TP53 等促凋亡因子缺失或基质微环境中促生存信号的支持等因素而不可避免地产生耐药性。通过 BH3 谱分析，我们发现与基质共培养的 CLL 细胞对 BCL-2 抑制诱导的凋亡的反应性较低。目前，临床上正在开发几种具有良好耐受性的口服药物来抑制 BCL-2。由于 BCL-XL 抑制，navitoclax（ABT-263）的剂量受到血小板减少的影响，但 BCL-2 特异性抑制剂 ABT-199（GDC-0199）应该可以避免这个问题，并且可能克服凋亡对基质介导的耐药性。我们正在开发 BH3 谱分析作为一种生物标志物，以预测对 ABT-199 等新型疗法的反应，并确定在 CLL 中研究的新药物的耐药机制。
