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Ong Sin Tiong

Associate Professor

Laboratory of Haematologic Malignancies

Email

Contact: 65167763

The research themes of this laboratory are translational in nature, and centre on gaining a better understanding of the basic pathophysiology of human malignancies in order to improve the management and treatment of patients with cancer.
 
Several projects in the laboratory are guided by the overarching hypothesis that dysregulated mRNA translation is essential to cellular transformation. This hypothesis is supported by prior work from our group and others which have demonstrated that the aberrant activation of several signaling pathways associated with the oncogenic state (including MAPK and PI3K/Akt) impinge on the cellular machinery that regulates both cap-dependent and cap–independent mRNA translation. These observations suggest that dysregulated translation contributes to cellular transformation via altering the expression of genes that control cellular proliferation and/or death. Importantly, these data indicate that therapeutic targeting of dysregulated translation is a valid strategy to test in the cancer clinic.
 
Specific projects in the laboratory include: investigating the role of cap-dependent and cap-independent translation in various human malignancies, the identification and development of small molecules which can target aberrant mRNA translation in cancer cells, and determining the identity of genes which are dysregulated at the level of translation. Other preclinical projects include the use of novel approaches to identify the molecular signature of drug resistance in primary human cancer tissues, as well as the genetic abnormalities that confer stem cell-like properties to human cancers, including the ability to self-renew. Finally, our group is also conducting an international Phase I study testing the feasibility and efficacy of targeting the mTOR kinase (a central regulator of eukaryotic mRNA translation) in patients with drug-resistant chronic myelogenous leukaemia.

Ko, T. K.;  Javed, A.;  Lee1, K. L.;  Pathiraja, T. N.;  Malik, X. L. S.;  Soh, S. X.;  Takahashi, X. T. H.;  Tan, J. H. J.;  Bhatia, R.;  Khng, A. J.;  Chng, W. J.;  Sia, Y. Y.;  Fruman, D. A.;  Ng, K. P.;  Chan, Z. E.;  Xie, K. J.;  Hoi, Q.;  Chan, C.;  Teo, A. S. M.;  Camacho, O. V.;  Meah, W. Y.;  Khor, C. C.;  Ong, C. T. J.;  Soon, W. J. W.;  Tan, P.;  Ng, P. C.;  Chuah, C.;  Hillmer, A. M.; Ong ST., An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood 10 March 2020. https://doi.org/10.1182/blood.2020004834

 

Sinnakannu, J. R.; Lee, K. L.;  Cheng, S.;  Li, J.;  Yu, M.;  Tan, S. P.;  Ong, C. C. H.;  Li, H.;  Than, H.;  Anczuków-Camarda, O.;  Krainer, A. R.;  Roca, X.;  Rozen, S. G.;  Iqbal, J.;  Yang, H.;  Chuah, C.; Ong ST., SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia 2020. doi: 10.1038/s41375-020-0732-1. [Epub ahead of print]

 

Takeuchi, S.;  Hase, T.;  Shimizu, S.;  Ando, M.;  Hata, A.;  Murakami, H.;  Kawakami, T.;  Nagase, K.;  Yoshimura, K.;  Fujiwara, T.;  Tanimoto, A.;  Nishiyama, A.;  Arai, S.;  Fukuda, K.;  Katakami, N.;  Takahashi, T.;  Hasegawa, Y.;  Ko, T. K.;  Ong ST.; Yano, S., Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double-positive lung cancer. Cancer science 111 (2), 561-570. 2020.

 

Than, H.;  Lye, W. K.;  Sng, C.;  Allen, J. C.;  Ong ST.; Chuah, C., BIM deletion polymorphism profiling complements prognostic values of risk scores in imatinib-treated Asian chronic myeloid leukemia patients. Leukemia & Lymphoma 60 (1), 234-237. 2019.

 

Christodoulou, E. G.;  Lee, L. M.;  Lee, K. L.;  Fung, T. K.;  So, E.;  Petretto, E.;  Ong ST.; Rackham, O. J., Identification of drugs for leukaemia differentiation therapy by network pharmacology. bioRxiv  676106. 2019.

 

Leidy-Davis, T.;  Cheng, K.;  Goodwin, L. O.;  Morgan, J. L.;  Juan, W. C.;  Roca, X.;  Ong ST.; Bergstrom, D. E., Viable Mice with Extensive Gene Humanization (25-kbp) Created Using Embryonic Stem Cell/Blastocyst and CRISPR/Zygote Injection Approaches. Scientific Reports  8 (1), 15028. 2018.

 

Rauzan M CC, Ko TK, Ong ST.  The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia. PLOS ONE 12 (3):e0174107, 2017.

 

Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, Ong ST, Yano S. Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib-resistance in EGFR-mutant lung cancer. Clinical Cancer Research 23(12):3139-3149, 2017.

 

Cherian J, Nacro K, Poh ZY, Guo S, Jeyaraj DA, Wong YX, Ho M, Yang HY, Joy JK, Kwek ZP, Liu B, Wee JLK, Ong EHQ, Choong ML, Poulsen A, Lee MA, Pendharkar V, Ding LJ, Manoharan V, Chew YS, Sangthongpitag K, Lim S, Ong ST, Hill J, Keller TH.  Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells. Journal of Medicinal Chemistry 59 (7):3063-3078, 2016.

 

Ko TK, Chin HS, Chuah CTH, Huang JWJ, Ng K-P, Khaw SL, Huang DCS, Ong ST.  The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia. Oncotarget 7 (3):2721-33, 2015.

 

Tsai BP, Jimenez J, Lim S, Fitzgerald KD, Zhang M, Chuah CTH, Axelrod H, Nelson L, Ong ST, Semler BL, Waterman ML.  A novel Bcr-Abl-mtor-eIF4a axis regulates IRES-mediated translation of LEF-1. Open Biology 4(11):140180, 2014.

 

Soh SX, Lim JYS, Huang JW, Jiang N, Yeoh AEJ, Ong ST.  Multi-Agent Chemotherapy Overcomes Glucocorticoid Resistance Conferred by a BIM Deletion Polymorphism in Pediatric Acute Lymphoblastic Leukemia. PLOS one 9 (8):e103435, 2014.

 

Ng KP, Manjeri A, Lee KL, Huang W, Tan SY, Chuah CTH, Poellinger L, Ong ST.  Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood 123 (21):3316-3326, 2014.

 

Ko TK, Chuah CTH, Huang JWJ, Ng K-P, Ong ST.  The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget 5 (19):9033-9038, 2014.

 

Juan WC, Roca X, Ong ST.  Identification of cis-Acting Elements and Splicing Factors Involved in the Regulation of BIM Pre-mRNA Splicing. PLOS ONE 9 (4):e95210, 2014.

 

Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, Lim AQ, Chang CT, Fruman DA, Rizzieri DA, Tan SY, Fan H, Chuah CTH, Ong ST.  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 110 (25):E2298-E2307, 2013.

 

Ng KP, Hillmer AM, Chuah CTH, Juan WC, Ko TK, Teo ASM, Ariyaratne PN, Takahashi N, Sawada K, Fei Y, Soh S, Lee WH, Huang JWJ, Allen Jr JC, Woo XY, Nagarajan N, Kumar V, Thalamuthu A, Poh WT, Ang AL, Mya HT, How GF, Yang LY, Koh LP, Chowbay B, Chang CT, Nadarajan VS, Chng WJ, Than H, Lim LC, Goh YT, Zhang S, Poh D, Tan P, Seet JE, Ang MK, Chau NM, Ng QS, Tan DSW, Soda M, Isobe K, Nöthen MM, Wong TY, Shahab A, Ruan X, Cacheux-Rataboul V, Sung WK, Tan EH, Yatabe Y, Mano H, Soo RA, Chin TM, Lim WT, Ruan Y, Ong ST.  A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Medicine 18 (4):521-528, 2012.

 

Juan WC, Ong ST.  The role of protein phosphorylation in therapy resistance and disease progression in chronic myelogenous leukemia. Prog Mol Biol Transl Sci 106:107-142, 2012.

 

Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, Vu C, Lilly MB, Mallya S, Ong ST, Konopleva M, Martin MB, Ren P, Liu Y, Rommel C, Fruman DA.  Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Medicine 16 (2):205-213, 2010.

 

Zhang M, Fu W, Prabhu S, Moore JC, Ko J, Kim JW, Druker BJ, Trapp V, Fruehauf J, Gram H, Fan HY, Ong ST.  Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Molecular and Cellular Biology 28 (20):6496-6509, 2008.

 

Prabhu S, Saadat D, Zhang M, Halbur L, Fruehauf JP, Ong ST.  A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene 26 (8):1188-1200, 2007.

 

Arechiga AF, Bell BD, Leverrier S, Weist BM, Porter M, Wu Z, Kanno Y, Ramos SJ, Ong ST, Siegel R, Walsh CM.  A Fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2 1. Journal of Immunology 179 (8):5291-5300, 2007.

 

 Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST.  Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Research 63 (18):5716-5722, 2003.