Chuah, Charles

MB, ChB (UK), MRCP (UK), MMed (Int Med), M.D. (London)

Assistant Professor

Cancer & Stem Cell Biology Programme

Other Affiliations:

Senior Consultant, Department of Haematology, Singapore General Hospital
Clinical Senior Lecturer, Yong Loo Lin School of Medicine, National University of Singapore
Director, Department of Clinical Translational Research, Singapore General Hospital
Director, Early Career Development Programme and Translational Research, Academic Clinical Program for Medicine, SingHealth-Duke-NUS
Director, Research, SingHealth Duke-NUS Blood Cancer Centre

+65 6321 4855

Email 1:

charleschuah@duke-nus.edu.sg

Research Bio Container

Research

Research Interest:

Our research focuses on the study of drug resistance in chronic myeloid leukaemia and strategies, both clinical and pre-clinical, to overcome resistance and to improve responses.

1. Detection of Abl kinase domain mutations in chronic myeloid leukaemia patients who are resistant to imatinib

The introduction of imatinib in 2000 has revolutionized the treatment of chronic myeloid leukaemia (CML), leading to highly effective responses with relatively low toxicities. However, resistance to the single drug therapy has also been observed. The most common mechanism of resistance is the development of mutations in the Abl kinase domain. Certain mutations remain totally resistant to imatinib, even at extremely high doses; while other mutations retain some sensitivity to imatinib and this resistance can be overcome by a higher dose of the drug. Imatinib-treated patients who harbour ATP-binding loop mutations also seem to have a worse survival outcome than those who have non-ATP-binding loop mutations. It would, therefore, be beneficial to the physician and the patient to know if this resistance is due to mutations in the Abl kinase domain and this knowledge would have useful therapeutic and prognostic implications.

2. A pre-clinical program to investigate novel compounds and strategies to target signalling pathways in chronic myeloid leukaemia

Bcr-Abl downstream pathways have been extensively studied and offer potential candidates for targeted therapy in CML. Simultaneous inhibition of signalling pathways at multiple levels may result in enhanced effectiveness and targeting a downstream effector may circumvent drug resistance. Based on this rationale, our project is designed to investigate if inhibition of Ras signalling, an important Bcr-Abl downstream pathway can overcome imatinib-resistance, and whether combining Ras inhibitors with Abl kinase inhibitors will be more effective in inhibiting proliferation and inducing apoptosis. Studies will be extended to mouse models to ascertain the effect on disease burden and survival. The biological effects of these inhibitors will also be investigated.

3. Clinical trials

We are currently participating in a number of multi-centre clinical trials using second-generation tyrosine kinase inhibitors in imatinib-resistant CML. We are also taking part in a phase 1 NIH/NCI-sponsored trial which investigates the combination of imatinib and an inhibitor of a Bcr-Abl downstream pathway.

Selected Publications:

Ko Tun Kiat; Chin Hui San; Chuah Charles T H; Huang John W J; Ng King-Pan; Khaw Seong Lin; Huang David C S; Ong S Tiong. The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia. Oncotarget 2016; 7(3):2721-2733.

Sun Wen Tian; Xiang Wei; Ng Bee Ling; Asari Kartini; Bunte Ralph M; Casey Patrick J; Wang Mei; Chuah Charles. Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia. Experimental Hematology 2015; e-Published Ahead of Print

Kwon Hyog Young; Bajaj Jeevisha; Ito Takahiro; Blevins Allen; Konuma Takaaki; Weeks Joi; Lytle Nikki K; Koechlein Claire S; Rizzieri David; Chuah Charles; Oehler Vivian G; Sasik Roman; Hardiman Gary; Reya Tannishtha. Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia. Cell Stem Cell 2015; 17(2):152-164.

Xiang Wei; Cheong Jit Kong; Ang Shi Hui; Teo Bryan; Xu Peng; Asari Kartini; Sun Wen Tian; Than Hein; Bunte Ralph M; Virshup David M; Chuah Charles. Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration. Oncotarget 2015; 6(32):33769-33780.

Chuah Charles T; Nakamae Hirohisa; Shen Zhixiang X; Bradley-Garelik M Brigid; Kim Dong-Wook. Efficacy and safety of dasatinib versus imatinib in the East Asian subpopulation of the DASISION trial of newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia & Lymphoma 2014; 55(9):2093-2100.

Jabbour Elias; Kantarjian Hagop M; Saglio Giuseppe; Steegmann Juan Luis; Shah Neil P; Boqué Concepción; Chuah Charles; Pavlovsky Carolina; Mayer Jirí; Cortes Jorge; Baccarani Michele; Kim Dong-Wook; Bradley-Garelik M Brigid; Mohamed Hesham; Wildgust Mark; Hochhaus Andreas. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123(4):494-500.

Zimdahl Bryan; Ito Takahiro; Blevins Allen; Bajaj Jeevisha; Konuma Takaaki; Weeks Joi; Koechlein Claire S; Kwon Hyog Young; Arami Omead; Rizzieri David; Broome H Elizabeth; Chuah Charles; Oehler Vivian G; Sasik Roman; Hardiman Gary; Reya Tannishtha. Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nature Genetics 2014; 46(3):245-252.

Ng King Pan; Manjeri Aditi; Lee Kian Leong; Huang Weijie; Tan Soo Yong; Chuah Charles T H; Poellinger Lorenz; Ong S Tiong. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood 2014; 123(21):3316-3326.

Ko Tun Kiat; Chuah Charles T H; Huang John W J; Ng King-Pan; Ong S Tiong. The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget 2014; 5(19):9033-9038.

Lim Sharon; Saw Tzuen Yih; Zhang Min; Janes Matthew R; Nacro Kassoum; Hill Jeffrey; Lim An Qi; Chang Chia-Tien; Fruman David A; Rizzieri David A; Tan Soo Yong; Fan Hung; Chuah Charles T H; Ong S Tiong. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proceedings of the National Academy of Sciences of the United States of America 2013; 110(25):2298-2307.

Cortes J E; Kim D-W; Pinilla-Ibarz J; le Coutre P; Paquette R; Chuah C; Nicolini F E; Apperley J F; Khoury H J; Talpaz M; DiPersio J; DeAngelo D J; Abruzzese E; Rea D; Baccarani M; Müller M C; Gambacorti-Passerini C; Wong S; Lustgarten S; Rivera V M; Clackson T; Turner C D; Haluska F G; Guilhot F; Deininger M W; Hochhaus A; Hughes T; Goldman J M; Shah N P; Kantarjian H. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. The New England Journal of Medicine 2013; 369(19):1783-1796.

Ng King Pan*; Hillmer Axel M*; Chuah Charles T H*; Juan Wen Chun*; Ko Tun Kiat; Teo Audrey S M; Ariyaratne Pramila N; Takahashi Naoto; Sawada Kenichi; Fei Yao; Soh Sheila; Lee Wah Heng; Huang John W J; Allen John C; Woo Xing Yi; Nagarajan Niranjan; Kumar Vikrant; Thalamuthu Anbupalam; Poh Wan Ting; Ang Ai Leen; Mya Hae Tha; How Gee Fung; Yang Li Yi; Koh Liang Piu; Chowbay Balram; Chang Chia-Tien; Nadarajan Veera S; Chng Wee Joo; Than Hein; Lim Lay Cheng; Goh Yeow Tee; Zhang Shenli; Poh Dianne; Tan Patrick; Seet Ju-Ee; Ang Mei-Kim; Chau Noan-Minh; Ng Quan-Sing; Tan Daniel S W; Soda Manabu; Isobe Kazutoshi; Nöthen Markus M; Wong Tien Y; Shahab Atif; Ruan Xiaoan; Cacheux-Rataboul Valère; Sung Wing-Kin; Tan Eng Huat; Yatabe Yasushi; Mano Hiroyuki; Soo Ross A; Chin Tan Min; Lim Wan-Teck; Ruan Yijun; Ong S Tiong. (*Authors contributed equally). A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Medicine 2012; 18(4):521-528.

Cortes Jorge; Lipton Jeff H; Rea Delphine; Digumarti Raghunadharao; Chuah Charles; Nanda Nisha; Benichou Annie-Claude; Craig Adam R; Michallet Mauricette; Nicolini Franck E; Kantarjian Hagop. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012; 120(13):2573-2580.

Nicolini Franck Emmanuel; Basak Grzegorz W; Soverini Simona; Martinelli Giovanni; Mauro Michael J; Müller Martin C; Hochhaus Andreas; Chuah Charles; Dufva Inge H; Rege-Cambrin Giovanna; Saglio Giuseppe; Michallet Mauricette; Labussière Hélène; Morisset Stéphane; Hayette Sandrine; Etienne Gabriel; Olavarria Eduardo; Zhou Wei; Peter Senaka; Apperley Jane F; Cortes Jorge. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood 2011; 118(20):5697-5700

Kantarjian Hagop; Shah Neil P; Hochhaus Andreas; Cortes Jorge; Shah Sandip; Ayala Manuel; Moiraghi Beatriz; Shen Zhixiang; Mayer Jiri; Pasquini Ricardo; Nakamae Hirohisa; Huguet Françoise; Boqué Concepción; Chuah Charles; Bleickardt Eric; Bradley-Garelik M Brigid; Zhu Chao; Szatrowski Ted; Shapiro David; Baccarani Michele. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. The New England Journal of Medicine 2010; 362(24):2260-2270.

Ito Takahiro; Kwon Hyog Young; Zimdahl Bryan; Congdon Kendra L; Blum Jordan; Lento William E; Zhao Chen; Lagoo Anand; Gerrard Gareth; Foroni Letizia; Goldman John; Goh Harriet; Kim Soo-Hyun; Kim Dong-Wook; Chuah Charles; Oehler Vivian G; Radich Jerald P; Jordan Craig T; Reya Tannishtha. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010; 466(7307):765-768.

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