A Novel Therapeutic Approach for Targeting CML Stem Cells

International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discoverry in Academics 2014 [DATE]: January 23(Thu)-24(Fri),2014, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Kanazawa Association of Tumor Biologists / Cancer Research Institute, Kanazawa Universit

Novel oral transforming growth factor-beta signaling inhibitor EW-7197 eradicates CML-initiating cells

Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-beta signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW-7197 to CML-affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW-7197 plus TKI was effective in eliminating CML-LICs even if they expressed the TKI-resistant T315I mutant BCR-ABL1 oncogene. Collectively, these results indicate that EW-7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML-LICs

TGF-β-FOXOシグナルによるがん幹細胞の制御機構の解明

金沢大学がん研究所研究課題/領域番号:23390065, 研究期間(年度):2011出典：研究課題「TGF-β-FOXOシグナルによるがん幹細胞の制御機構の解明」課題番号23390065（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-23390065/）を加工して作

正常組織幹細胞を指標とするがん幹細胞特定マウスモデルの構築

金沢大学がん進展制御研究所がんには増殖するがん細胞の供給源となるがん幹細胞が少数存在し,がんの転移,浸潤,播種や薬剤耐性の再発の原因となる可能性が指摘されている.このがん幹細胞を個体内で標識し,同定する技術は,がん幹細胞を標的とするがん治療法を開発するうえで必要不可欠である.このようながん幹細胞を同定可能な動物モデルを作出するため,平成18年度は正常組織幹細胞で特異的に発現誘導される遺伝子のプロモーター/エンハンサー領域の下流でgreen fluorescence protein(GFP)を発現するトランスジェニック(Tg)マウスを樹立し,このTgマウスシステムを用いてマウス急性骨髄性白血病モデルにおける白血病幹細胞の同定を試みた.平成19年度は,このマウス急性骨髄性白血病モデルの白血病幹細胞において正常組織幹細胞発現遺伝子が高発現していることを見いだした.この正常組織幹細胞発現遺伝子の白血病幹細胞における発現意義を解明するため,RNA干渉法による発現抑制を検討した.その結果,この遺伝子の発現抑制によって白血病幹細胞のin vitroでの増殖能の低下,並びにin vivoでの白血病発症の遅延を認めた.従って,この正常組織幹細胞発現遺伝子が白血病幹細胞の増殖に重要な役割を担っている可能性がある.一方,白血病幹細胞が薬剤耐性の再発に関与しているか検討するため,白血病を発症したマウスに抗がん剤5-FUの投与を行った.その結果,白血病再発時に白血病幹細胞集団の著しい増殖を認め,白血病幹細胞が白血病再発の原因となる可能性が示唆された.以上のような結果から,このTgマウスを用いた白血病幹細胞同定システムは白血病幹細胞の特性を解析する上で有用であると考えられる.研究課題/領域番号:18790268, 研究期間(年度):2006 – 2007出典：「正常組織幹細胞を指標とするがん幹細胞特定マウスモデルの構築」研究成果報告書　課題番号18790268（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-18790268/)を加工して作

Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity

Division of Molecular Genetic

Foxo3a is essential for maintenance of the hematopoietic stem cell pool

Division of Molecular Genetic

Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells

がん進展制御研究所Although discovery of the tyrosine kinase inhibitor (TKI) imatinib mesylate has significantly improved the prognosis of chronic myeloid leukemia (CML) patients, a rare population of CML stem cells is known to be resistant to TKI therapy, causing recurrence of CML. However, recent progress in CML stem cell biology may present a novel therapeutic avenue for CML patients. In this review, we focus on mechanisms used by CML stem cells to maintain TKI-resistance. Comprehensive approaches including mouse genetics, prospective identification of CML stem cells, and syngenic transplantation techniques have identified several key molecules or signaling pathways, including hedgehog (Hh)/Smo, promyelocytic leukemia (PML), 5-lipoxygenase (5-LO), and forkhead box class O (FOXO), that function in CML stem cell maintenance. Inhibiting some of these factors in combination with TKI administration successfully antagonized resistance of CML stem cells to TKI therapy, resulting in efficient eradication of leukemia cells in vivo. Thus, development of methods that sensitize CML stem cells to TKI therapy may lead to novel therapies to treat CML patients. © 2010 Japanese Cancer Association

Ablation of Fbxw7 Eliminates Leukemia-Initiating Cells by Preventing Quiescence

SummaryImatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML

Crosstalk between the Rb Pathway and AKT Signaling Forms a Quiescence-Senescence Switch

SummaryCell-cycle arrest in quiescence and senescence is largely orchestrated by the retinoblastoma (Rb) tumor-suppressor pathway, but the mechanisms underlying the quiescence-senescence switch remain unclear. Here, we show that the crosstalk between the Rb-AKT-signaling pathways forms this switch by controlling the overlapping functions of FoxO3a and FoxM1 transcription factors in cultured fibroblasts. In the absence of mitogenic signals, although FoxM1 expression is repressed by the Rb pathway, FoxO3a prevents reactive oxygen species (ROS) production by maintaining SOD2 expression, leading to quiescence. However, if the Rb pathway is activated in the presence of mitogenic signals, FoxO3a is also inactivated by AKT, thus reducing SOD2 expression and consequently allowing ROS production. This situation elicits senescence through irreparable DNA damage. We demonstrate that this pathway operates in mouse liver, indicating that this machinery may contribute more broadly to tissue homeostasis in vivo