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Laboratory of Molecular Carcinogenesis

​Research head:​Professor Kanaga SABAPATHY
​Research team:

​Dr Ramesh KUMAR

Dr Dan LI

Dr Ifeoma UBBY

Dr Chao WANG

Dr Bahareh TABANIFAR

Beng Hooi PHANG

Tarini d/o SUBRAMANIAM

Rashidah Binte OTHMAN

Shengyang QU

Catherine KOK

Derrick CHIA

Ni PENG

Kamaliyah Binte ABDULLAH

Cui Rong TEO

Fanny TEO

Christian Heiko KRUEGER

The Sabapathy lab is focused on understanding the mechanistic basis of cancer development and resistance to therapeutic drugs, and translating the findings to generate effective therapies for cancer. To this end, multiple, nationally funded projects are undertaken by the team, as described:


GENERATION AND CHARACTERISATION OF MOUSE MODELS FOR CANCERS


Based on our expertise in generating and analysing genetically modified mice, we have been focusing on: 1) Understanding the development of liver cancers, especially those that arise in conjunction with hepatitis B virus, so as to identify biomarkers for early detection, and altered molecular pathways for therapeutic targeting; 2) Generating mouse models to recapitulate the development of liposarcomas for testing novel treatment modalities; and 3) understanding the cellular basis of breast cancer development, with a particular focus on the role of the stromal microenvironment in contributing to breast neoplasms. The use of mouse as a model organism has provided us with significant advantages in our understanding of multiple cancer types.

TARGETING P53 FAMILY MEMBERS


p53 is the most commonly mutated gene in cancers. However, due to enormous technical difficulties, there are currently no therapies available to target mutant p53. Our efforts over the years have led to the characterisation of the various p53 mutants identified in humans, which has led to the concept of the “rainbow of p53 mutants” (Figure 1), all of which display varying degrees of oncogenic potential. Based on this concept, we have developed novel, first-in-class mutation-specific antibodies that are useful in the clinical diagnosis of mutants. We are working towards utilising these antibodies, as well as mutation-specific siRNAs, to target mutant p53 to improve treatment. Similar work is also underway to understand the functions of p73, the homologue of p53, to target its oncogenic functions in tumours.


Figure 1: “Rainbow of p53 mutants”. This "rainbow” is based on the capacity of p53 mutants to differentially transactivate target genes when expressed on a p53-null
background, except in the case of DBD-DN mutants, which relates to the heterozygous state. WT and mutant p53 monomers are represented in yellow and red, respectively. PF, partial function; p53RE, p53 response element; TFRE, transcription-factor response element.

Selected publications:

  1. Dulloo I, Phang BH, Othman R, et al. Hypoxia-inducible TAp73 regulates the angiogenic transcriptome and supports tumorigenesis. Nat Cell Biol. 2015;17:511–523.
  2. Phang BH, Othman R, Bougeard G, et al. Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis. Proc Natl Acad Sci U S A. 2015;112:E6349–E6358.
  3. Huang MN, Yi W, Teoh WW, et al. Genome-wide AFB1-induced mutational signatures in cells, mice and human tumors – implications for molecular epidemiology. Genome Biol. 2017;27:1475–1486.
  4. Sabapathy K and Lane DP. p53: all mutants are equal, but some mutants are more equal than others – therapeutic considerations for targeting mutant p53. Nat Rev Clin Oncol. 2018;15:13–30.
  5. Hwang LA, Phang BH, Liew OW, et al. Novel tools for precision medicine– monoclonal antibodies against specific p53 hot-spot mutants. Cell Rep. 2018;22:299–312.