Chuah, Charles

Research Interests:

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:

Pavlu J, Andreasson C, Chuah C et al. Dual inhibition of ras and bcr-abl signalling pathways in chronic myeloid leukaemia: a phase I/II study in patients in complete haematological remission. Br.J.Haematol. 2007;137:423-428.

Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249:121-132.

Chuah C, Lim TH, Lim AS et al. Dasatinib induces a response in malignant thymoma. J.Clin.Oncol. 2006;24:e56-e58.

Gullo CA, Chuah CT, Hwang WY, Teoh GK. Detection and quantification of the abelson tyrosine kinase domains of the BCR-ABL gene translocation in chronic myeloid leukaemia using genomic quantitative real-time polymerase chain reaction. Ann.Acad.Med.Singapore 2006;35:680-687.

Melo JV, Chuah C. Molecular basis of resistance to imatinib. Hematology - The European Hematology Association Education Program 2006;2:86-92.

Chuah C, Barnes DJ, Kwok M et al. Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells. Leukemia 2005;19:1896-1904.

Chuah C, Melo JV. Resistance to imatinib mesylate in chronic myeloid leukaemia: mechanisms and approaches to overcome it. BloodMed.com 2005

Koh LP, Hwang WY, Chuah CT et al. Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis. Bone Marrow Transplant. 2003;31:305-308.

Koh LP, Hwang WY, Tan CH et al. Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling-evaluation of risks and benefits. Ann.Hematol. 2004;83:286-294.