演題詳細

一般口演 / Oral Session

【E】一般口演 19 (Oral Session 19) :AML:Mechanism of Therapeutic Agent

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日程
2013年10月11日(金)
時間
14:25 - 15:25
会場
第4会場 / Room No.4 (さっぽろ芸文館 3F 黎明)
座長・司会
小林 正夫 (Masao Kobayashi):1
1:Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
 
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Efficacy and biomarker analyses of treatment with the Hedgehog inhibitor, PF-04449913, in AML cells

演題番号 : OS-1-99

福島 庸晃 (Nobuaki Fukushima):1、南 陽介 (Yosuke Minami):2、直江 知樹 (Tomoki Naoe):1

1:Dept of Hematology and Oncology, Nagoya Univ、2:Division of Blood Transfusion / Division of Oncology and Hematology, Kobe Univ Hospital

 

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers and maintenance of leukemic stem cells. A novel Smoothened (SMO) inhibitor, PF-04449913 (PF) treatment has shown promising results regarding safety and early signs of efficacy in the clinical study for AML. In order to elucidate mechanisms and biomarkers during PF treatment, we used AML cell lines and primary cells. We also used a co-culturing system with HS-5 stromal cells, and an immunodeficient NOG mouse model serially xenotransplanted with primary AML cells to evaluate effects of PF on AML propagation. In vivo-treatment with PF attenuated leukemia-initiation potential in AML cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Ex vivo-treatment with PF inhibited proliferation and minimally induced cell death in leukemia cell lines and primary AML cells increased expression of the myeloid differentiation marker. In addition, PF treatment down-regulated mRNAs encoding downstream effector GLIs in the canonical Hh pathway using RQ-PCR assays and decreased nuclear expression of GLI-2 using immunofluorescence assays. Moreover, combined treatment with PF abrogated resistance to Ara-C in MOLM-14 cells co-cultured with HS-5 stromal cells. We are also investigating biomarkers in these models including CD markers. These results imply that PF treatment can attenuate leukemia-initiation potential in AML cells and improve AML therapy through overcoming the resistance to chemotherapy in the bone marrow microenvironment.

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