Ong, Sin Tiong

Research Interests:

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.

Selected Publications:

Ong ST, DeGroot LJ, Vogelzang NJ. Phase II evaluation of single agent carboplatin in advanced thyroid cancer. Oncology Reports, 1/6:1217-1218, 1994.

Rassool FV, Le Beau MM, Shen ML, Neilly ME, Espinosa R, Ong ST, Boldog F, Drabkin H, McKeithan TW. Direct cloning of DNA sequences from the common fragile site region at chromosome band 3p14.2. Genomics, 351(1):109-117, 1996.

Fong KM, Biesterveld EJ, Virmani A, Wistuba I, Sekido Y, Bader SA, Ahmadian M, Ong ST, Rassool FV, Zimmerman PV, Giaccone G, Gazdar AF, Minna JD. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer related FHIT cDNA splicing aberrations. Cancer Research, 57(11):2256-2267,1997.

Ong ST, Fong KM, Bader SA, Minna JD, Le Beau MM, McKeithan TW, Rassool FV. Precise localization of the FHIT gene to the common fragile site at 3p14.2 (FRA3B), and characterization of homozygous deletions within FRA3B that affect FHIT transcription in tumor cell lines. Genes, Chromosomes and Cancer, 20(1):16-23, 1997.

Ong ST, Hackbarth ML, Degenstein LC, Baunoch DA, Anastasi JA, McKeithan TW. Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice. Oncogene, 16, 2333-2343, 1998.

Peters UR, Hasse U, Oppliger E, Tschan M, Ong ST, Rassool FV, Borisch B, Tobler A, Fey MF. Aberrant FHIT mRNA transcripts are present in malignant and normal haematopoiesis, but absence of FHIT protein is restricted to leukaemia. Oncogene, 18(1):79-85, 1999.

Ong ST, Ly C, Nguyen M, Brightman K, Fan H. Expression profiling of a transformed thycocyte cell line undergoing maturation in vitro identifies multiple genes involved in positive selection. Cellular Immunology, 221, 64-79, 2003.

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 mTOR. Cancer Research, 63: 5716-5722, 2003.

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

Arechiga AF, Bell BD, Porter M, Wu Z, Kanno Y, Ramos .J, Ong ST, Siegel RM, Walsh CM. A FADD/Caspase-8 signaling axis promotes S-phase entry and maintains S6 kinase activity. Journal of Immunology, 179:5291-300, 2007.

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

Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. 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. Nature Medicine, in press, 2010.