Hiroaki Goto1, Yuki Yoshino2, Mieko Ito2, Junichi Nagai3, Tadashi Kumamoto4, Takesi Inukai5, Yukari Sakurai2, Naoyuki Miyagawa2, Dai Keino2, Tomoko Yokosuka2, Fuminori Iwasaki2, Satoshi Hamanoue2, Masae Shiomi2, Shoko Goto2. 1. Division of Hematology/Oncology, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa Minami-Ku, Yokohama, Japan. hgotou@kcmc.jp. 2. Division of Hematology/Oncology, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa Minami-Ku, Yokohama, Japan. 3. Department of Laboratory Medicine, Kanagawa Children's Medical Center, Yokohama, Japan. 4. Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan. 5. Department of Pediatrics, School of Medicine, Yamanashi University, Kofu, Japan.
Abstract
PURPOSE: Acute lymphoblastic leukemia (ALL) is curable with standardized chemotherapy. However, the development of novel therapies is still required, especially for patients with relapsed or refractory disease. By utilizing an in vitro drug screening system, active molecular targeting agents against ALL were explored in this study. METHODS: By the in vitro drug sensitivity test, 81 agents with various actions were screened for their cytotoxicity in a panel of 22 ALL cell lines and ALL clinical samples. The drug effect score (DES) was calculated from the dose-response of each drug for comparison among drugs or samples. Normal peripheral blood mononuclear cells were also applied onto the drug screening to provide the reference control values. The drug combination effect was screened based on the Bliss independent model, and validated by the improved isobologram method. RESULTS: On sensitivity screening in a cell line panel, barasertib-HQPA which is an active metabolite of barasertib, an aurora B kinase inhibitor, alisertib, an aurora A kinase inhibitor, and YM155, a survivin inhibitor, were effective against the broadest range of ALL cells. The DES of barasertib-HQPA was significantly higher in ALL clinical samples compared to the reference value. There were significant correlations in DES between barasertib-HQPA and vincristine or docetaxel. In the drug combination assay, barasertib-HQPA and eribulin showed additive to synergistic effects. CONCLUSION: Aurora B kinase was identified to be an active therapeutic target in a broad range of ALL cells. Combination therapy of barasertib and a microtubule-targeting drug is of clinical interest.
PURPOSE:Acute lymphoblastic leukemia (ALL) is curable with standardized chemotherapy. However, the development of novel therapies is still required, especially for patients with relapsed or refractory disease. By utilizing an in vitro drug screening system, active molecular targeting agents against ALL were explored in this study. METHODS: By the in vitro drug sensitivity test, 81 agents with various actions were screened for their cytotoxicity in a panel of 22 ALL cell lines and ALL clinical samples. The drug effect score (DES) was calculated from the dose-response of each drug for comparison among drugs or samples. Normal peripheral blood mononuclear cells were also applied onto the drug screening to provide the reference control values. The drug combination effect was screened based on the Bliss independent model, and validated by the improved isobologram method. RESULTS: On sensitivity screening in a cell line panel, barasertib-HQPA which is an active metabolite of barasertib, an aurora B kinase inhibitor, alisertib, an aurora A kinase inhibitor, and YM155, a survivin inhibitor, were effective against the broadest range of ALL cells. The DES of barasertib-HQPA was significantly higher in ALL clinical samples compared to the reference value. There were significant correlations in DES between barasertib-HQPA and vincristine or docetaxel. In the drug combination assay, barasertib-HQPA and eribulin showed additive to synergistic effects. CONCLUSION: Aurora B kinase was identified to be an active therapeutic target in a broad range of ALL cells. Combination therapy of barasertib and a microtubule-targeting drug is of clinical interest.
Entities:
Keywords:
Acute lymphoblastic leukemia; Aurora B kinase; Barasertib; In vitro drug sensitivity test; Survivin
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