LEONG CHEE ONN

Designation/Title : Associate Professor
Department: School of Pha
Tel: 03-2731 7528
Mobile : 012 208 5170
Fax : 03-8656 7229
E-mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it

 

Education and Training

Associate Professor International Medical University (IMU) Present
Senior Lecturer International Medical University (IMU) 2001
Research Fellow
Harvard Medical School, Boston, USA 2008
PhD University of Nottingham, UK
2003
BSc
University Putra Malaysia
2000

 

Research interests:

  • p53, p63 and p73 Networks in Breast Cancers
    Our work concerns the fundamental mechanisms of human epithelial tumorigenesis. We focus on the p53 gene family, members of which are among the most prominent genes in human cancer biology. The recent identification of two p53-related genes, p63 and p73, has provided new insight into the diverse functions of this gene family in development and cancer. We are currently using multiple approaches to understand the biochemical properties of the p63 protein, its interactions with p53 and p73, and its functional role in development and cancer. We showed that triple-negative breast cancer (ER, PR and HER2-negative) specimens express increased amounts of p63 and p73. p63 was shown to bind p73 and prevent it from killing the cancerous cells. Importantly, the chemotherapeutic drug cisplatin, but not other commonly used chemotherapeutic drugs, was found to release p73 from p63, causing the cells to be killed. This study indicates that individuals with triple-negative breast cancer might benefit from early treatment with cisplatin if their cancerous cells express increased amounts of p63 and p73.

    Our success in defining novel functional interactions within the p53 family provides new therapeutic possibilities for a variety of treatment-refractory malignancies. We are currently developing high-throughput approaches to identify specific therapeutic targets within the critical pathways we have uncovered. Through collaborations with academic and industry partners we seek to rapidly develop and test the new treatments that may emerge based on our basic science discoveries.

  • Mechanisms of p53 Mutants Gain-of-Function p53 is the most commonly mutated tumour-suppressor gene in human cancers. Unlike other tumour-suppressor genes, most p53 cancer mutations are missense mutations within the core domain, leading to the expression of full-length mutant p53 protein. Accumulating evidence has indicated that p53 cancer mutants not only lose the tumour suppression activity, but also gain new oncogenic activities to promote tumourigenesis. Recent evidence convincingly shows that such mutant p53 proteins promote tumourigenesis through both dominant-negative and “gain of function” properties. Nevertheless, the mechanism of mutant p53 function remains controversial.

    By employing RNA interference (RNAi) approach, we have investigated the functional role of mutant p53 in human breast cancer cells. We show that silencing of mutant p53 in T47D and MDA-MB-468 cells induced massive apoptosis. Although one postulated mechanism for a dominant effect of mutant p53 is through inhibition of p63 and/or p73, the apoptosis induced by mutant p53 knock-down in breast cancer cells is independent of p63 or p73 function. Since both T47D and MDA-MB-468 cells express only mutant p53, our findings also demonstrate that the effect we observe is not due to the dominant-negative function of mutant p53 toward wild-type p53. Taken together, these findings suggest a role for mutant p53 in mediating the survival of human breast cancer cells through novel transcriptional regulation of oncogenic pathways. Given the active role of mutant p53 proteins in promoting tumourigenesis and their very common occurrence in human cancer, identification of pathways regulated by distinct classes of mutant p53 proteins may provide new therapeutic targets that would improve the treatment of patients with refractory cancers.

  • Identification of new molecular targets and development of effective combination therapies for treatment of refractory breast and nasopharyngeal carcinomas (NPC)
    Developing specific therapeutics for treatment of breast and nasopharyngeal carcinoma has been a challenge that has met with only limited clinical success. Despite the challenges, therapies addressing fundamental genetic defects within the malignant cell hold tremendous promise for the future treatment of cancers. Human kinases play an integral role in signal transduction involving cell development, differentiation, proliferation and apoptosis. As such, kinase inhibitors such as Imatinib, Iressa and Herceptin have been used successfully in treating various types of cancers in the clinics. In our laboratory, we devised a rapid and innovative approach to identify “drugable” pathways that regulate the survival of breast and nasopharyngeal carcinoma cells. Using a comprehensive RNA interference (RNAi) screen, we identified number of endogenous kinases whose inhibition will induce apoptosis specifically in tumour cells. Extensive direct validation of candidate kinases identified through this screen is currently being carried out. Two such targets are mTOR and BCL2 whose inhibition synergized cisplatin sensitivity in breast and nasopharyngeal carcinoma cells, respectively. Thus, molecules identified through this screen will promise to be attractive therapeutic targets for future treatment of this refractory disease.

  • Development of siRNA-based therapeutics for treatment of human cancers
    With increasing knowledge on the molecular mechanisms of endogenous RNA interference, small interfering RNAs (siRNAs) have been emerging as innovative nucleic acid medicines for treatment of incurable diseases such as cancers. Although several siRNA candidates for the treatment of ocular and respiratory diseases are undergoing clinical trials, there are challenges inherent in the further development of siRNAs for therapeutics purposes, because systemic administration will be required in most cases. Appropriate delivery remains a major hurdle.
    The recent discovery of carbon nanotubes has stimulated intense interest in many areas including nanomedicine. One of the key advantages of carbon nanotubes in biomedical applications is that they can be easily internalized by cells, and therefore can act as delivery vehicles for a variety of biomolecules. Although the delivery of siRNA using carbon nanotubes has been demonstrated recently, its efficacy was not satisfactory due to its inherent toxicity and low release rate of siRNA into the cytoplasm. To over come these challenges, better undertanding of the interactions between carbon nanotubes chemistry and biological system need to be further explored. As such, our research tem is currently addressing the fundamental issues of carbon nanotube-based siRNA delivery system by investigating the effects of surface chemistry on siRNA delivery mechanism and efficacy, in vivo phamacokinetic and biodistribution, mechanism of nanotoxicity, and metabolic pathway disruptions. Results obtained from this study will undoubtedly lead to the development of safer nanotubes for biomedical applications and a more efficient siRNA delivery system.


Research projects/grants:

  • Systemic delivery of siRNA-based therapeutics using functionalized single-walled carbon nanotubes (SWNTs)
    MOSTI Nanotechnology Fund, Malaysia (Principal Investigator)
  • The Role of BCL2 Family Proteins in Mutant p53 “Gain of Function”
    MoHE FRGS,Malaysia (Principal Investigator)
  • Molecular target and mechanism of action of F8268, a novel and potent antitumor compound isolated from an endophytic Aspergillus.
    MoHE FRGS, Malaysia (Co-investigator)
  • Rapid identification of new molecular targets for treatment of refractory breast cancers
    MOSTI eScience Fund, Malaysia (Principal Investigator)
  • Targeting mutant p53 for treatment of basal-like breast cancers
    MAKNA Cancer Research Award, Malaysia (Principal Investigator)
  • Novel regulatory mechanisms for p53-independent apoptosis in tumor cells
    ECOR Fund for Medical Discovery, USA (Principal Investigator)



Supervision of Postgraduates (MSc/PhD)
(Last 5 years – 2008-2012)

  • Mr Tan Boon Shing – PhD. (2012 - Present) - Chief Supervisor
    Role of mutant p53 in cellular anoikis.
  • Ms Tiong Kai Hung – PhD. (2010 - Present) - Chief Supervisor
    Identification of new molecular targets for treatment of basal-like breast cancers.
  • Mr Choo Heng Lungh – PhD. (2010 - Present) - Chief Supervisor
    Targeting the human kinome in nasopharyngeal carcinomas.
  • Ms Ong Li Chu – MSc. (2011 - Present) - Chief Supervisor
    Nanotoxicity of Pristine and Functionalized Single-Wall Carbon Nanotubes (SWNTs)
  • Mr Tan Boon Shing – MSc. (2010 - 2012) - Chief Supervisor
    Mechanism of mutant p53 gain-of-function effects in human breast cancers
  • Ms Nor Nadia Ban – MSc. (UiTM, 2010 - present) – Co-Supervisor
    Molecular target and mechanism of action of F8268, a novel and potent antitumor compound isolated from an endophytic Aspergillus.


Professional affiliations:

  • British Association for Cancer Research (Member)
  • European Association for Cancer Research (Member)
  • American Association for Cancer Research (Associate Member)
  • Malaysian Society for Molecular Biology and Biotechnology (Member)
  • Malaysian Society of Nasopharyngeal Carcinoma (Member)

Academic Awards:

  • 10th International Conference of the Asian Clinical Oncology Society (ACOS) Travel Award, Korea
  • MAKNA Cancer Research Award (Malaysia)
  • Best presentation award (3rd Regional Conference on Molecular Medicine 2009, Malaysia)
  • ECOR Fund for Medical Discovery Fellowship Award (USA)
  • Best poster and oral presentation award (4th Annual Symposium of the Dana-Farber/Harvard Cancer Center Program in Breast Cancer, Boston, USA).
  • Best poster presentation award (Annual Scientific Advisory Board Meeting for Cancer Research, USA)
  • Overseas Research Student Awards Scheme (ORS) - University of Nottingham, UK
  • International Biomedical Society Young Scientist Award - Institute of Biomedical Sciences, UK
  • Best Student of the Year - Roche Inc.
  • Best Academic Achievement (Pharmacology) – Pfizer
  • Best Academic Achievement (Human Physiology)
  • Best Academic Achievement (Human Nutrition)

Recent publications
(last 5 years – 2008 -2012)

Journal

  • Low SY, Tan BS, Choo HL, Tiong KH, Khoo AS, Leong CO: Suppression of BCL-2 synergizes cisplatin sensitivity in nasopharyngeal carcinoma cells. Cancer Lett 2012, 314(2):166-175. (IF = 4.864)
  • Tan BS, Tiong KH, Muruhadas A, Randhawa N, Choo HL, Bradshaw TD, Stevens MF, Leong CO: CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells. Mol Cancer Ther 2011, 10(10):1982-1992. (IF = 5.225, cited by 2)
  • Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, Lee CY, Quah SI, Fow C, Chung C et al: Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73. Breast Cancer Res Treat 2011, 128(2):301-313. (IF = 4.859, cited by 11)
  • Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A et al: Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol 2010, 28(7):1145-1153. (IF = 18.970, cited by 180)
  • Ibrahim N, He L, Leong CO, Xing D, Karlan BY, Swisher EM, Rueda BR, Orsulic S, Ellisen LW: BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma. Cancer Res 2010, 70(18):7155-7165. (IF = 8.234, cited by 14)
    Lim LY, Vidnovic N, Ellisen LW, Leong CO: Mutant p53 mediates survival of breast cancer cells. Br J Cancer 2009, 101(9):1606-1612. (IF = 4.831, cited by 16)
  • Bradshaw TD, Wren JE, Bruce M, Barrett DA, Leong CO, Gaskell M, Wright EK, Farmer PB, Henderson CJ, Wolf R et al: Preclinical toxicokinetic evaluation of phortress [2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole lysylamide dihydrochloride] in two rodent species. Pharmacology 2009, 83(2):99-109. (IF = 1.802, cited by 3)
  • Miao J, Wang Z, Provencher H, Muir B, Dahiya S, Carney E, Leong CO, Sgroi DC, Orsulic S: HOXB13 promotes ovarian cancer progression. Proc Natl Acad Sci U S A 2007, 104(43):17093-17098. (IF = 9.771, cited by 33)
  • Bradshaw TD, Stone EL, Trapani V, Leong CO, Matthews CS, te Poele R, Stevens MF: Mechanisms of acquired resistance to 2-(4-Amino-3-methylphenyl)benzothiazole in breast cancer cell lines. Breast Cancer Res Treat 2008, 110(1):57-68. (IF = 4.859, cited by 11)
  • Leong CO, Vidnovic N, DeYoung MP, Sgroi D, Ellisen LW: The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest 2007, 117(5):1370-1380. (IF = 14.152, cited by 120)
  • DeYoung MP, Johannessen CM, Leong CO, Faquin W, Rocco JW, Ellisen LW: Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma. Cancer Res 2006, 66(19):9362-9368. (IF = 8.234, cited by 53)
  • Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW: p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol 2006, 8(6):551-561. (IF = 19.407, cited by 180)
  • Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW: p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 2006, 9(1):45-56. (IF = 26.925, cited by 194)
  • Leong CO, Suggitt M, Swaine DJ, Bibby MC, Stevens MF, Bradshaw TD: In vitro, in vivo, and in silico analyses of the antitumor activity of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazoles. Mol Cancer Ther 2004, 3(12):1565-1575. (IF = 5.225, cited by 40)
  • Leong CO, Gaskell M, Martin EA, Heydon RT, Farmer PB, Bibby MC, Cooper PA, Double JA, Bradshaw TD, Stevens MF: Antitumour 2-(4-aminophenyl)benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo. Br J Cancer 2003, 88(3):470-477. (IF = 4.831, cited by 50)
  • Trapani V, Patel V, Leong CO, Ciolino HP, Yeh GC, Hose C, Trepel JB, Stevens MF, Sausville EA, Loaiza-Perez AI: DNA damage and cell cycle arrest induced by 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is attenuated in aryl hydrocarbon receptor deficient MCF-7 cells. Br J Cancer 2003, 88(4):599-605. (IF = 4.831, cited by 52)







 

This e-mail address is being protected from spambots. You need JavaScript enabled to view it
 

MS ISO/IEC 17025
TESTING
SAMM NO.650