Therapeutic targeting of p53

TP53 is the most frequently mutated gene across all cancer types. The presence of mutant p53 predisposes to cancer development, promotes the survival of cancer cells, and is associated with ineffective therapeutic responses and unfavourable prognoses. Despite these effects, no drug that abrogates the oncogenic functions of mutant p53 has been approved for the treatment of cancer. Current investigational therapeutic strategies are mostly aimed at restoring the wild-type activity of mutant p53, underscored by the assumption that all p53 mutants are functionally equal. Our increasing knowledge of mutant forms of p53, however, supports the antithetical hypothesis that not all p53 mutants have equivalent cellular effects; hence, a judicious approach to therapeutic targeting of mutant p53 is required. In this talk, I’ll propose a categorization of the major classes of p53 mutants based on their functionality in tumour suppression and response to therapy. The emerging picture is that the mutations across TP53 form a ‘rainbow of mutants’, with varying degrees of functionality and different pathobiological consequences, necessitating the use of diverse therapeutic strategies to selectively target specific classes of mutation, which will be discussed.


About Kanaga Sabapathy

Kanaga Sabapathy obtained his B.Sc (Hons) degree in Zoology from the National University of Singapore (NUS), and then his Ph.D. in Molecular & Cellular Immunology from the Institute for Molecular & Cellular Biology (IMCB), Singapore, in 1995. His post-doctoral work was conducted at the Institute of Molecular Pathology in Vienna with Dr Erwin Wagner, studying the c-Jun-N-terminal kinase stress signaling pathway, using genetically-engineered mice.  He moved to the National Cancer Centre Singapore (NCCS) in late 1999 as the Principal Investigator of the Laboratory of Molecular Carcinogenesis, and since 2013, is the overall Head of the Division of Cellular & Molecular Research.  He is also the Research Director of the Academic Clinical Program in Oncology at SingHealth-Duke-NUS.  Dr Sabapathy is a Professor with the Cancer and Stem Cell Biology Program at Duke-NUS; a joint Professor with the Department of Biochemistry at NUS and a joint Research Director at the IMCB. He is a Fellow of the Royal College of Pathologists (UK), and was awarded the inaugural National Research Foundation Investigatorship award (Class of 2015). He has recently been appointed as the Director of Planning and Strategy at the NCCS, to coordinate and oversee all brand planning, strategic planning and analytical activities in the upcoming new NCCS.

Dr Sabapathy’s group focuses on investigating the molecular mechanisms involved in cancer development and response to therapy, through the study of the p53 and p73 tumor suppressor paradigms.   His research is aimed at both understanding the molecular nature of cancer and designing effective targeted-therapies against the disease.