Ashok VENKITARAMAN

• NRF Open Fund-Large Collaborative Grant (OF-LCG) 
• NMRC Open Fund-Large Collaborative Grant (OF-LCG) 
• MOE Academic Research Fund (AcRF)
• Gray Foundation Team Science Award

RESEARCH

My lab’s overall goal is to understand the mechanisms underlying susceptibility to cancer, and to exploit this knowledge in innovative approaches for early clinical intervention in the commonest human cancers. We focus on scientific questions rather than methodological approaches, and deploy or invent new technologies where required to address such questions.

To understand cancer susceptibility, we use inherited mutations in the BRCA2 gene as a powerful model system. My lab was amongst the first to discover the biological functions of BRCA2 in genome maintenance underlying its role as a tumour suppressor, to lay the foundations for the targeted therapy of BRCA-deficient cancers, and to reveal metabolic mechanisms that ‘bypass’ tumour suppression to initiate carcinogenesis. 

To develop innovative approaches for clinical intervention, my lab has devised powerful new technology platforms to identify and validate therapeutic targets in complex pathways (Protein-interference), to modulate enzyme activity using small-molecule ligands outwith the catalytic site via regulatory protein-protein interactions (allo-targeting), and to interrogate cellular signaling pathways using new tools in light microscopy (e.g. hyper-dimensional imaging microscopy). These technology innovations have led to serial Cambridge University spin-out companies (PhoreMost Ltd., Sentinel Oncology Ltd.), which have reached clinical impact through ongoing clinical trials of new drugs. 

Our ongoing research has revealed metabolic triggers and environmental cues that modulate early steps in carcinogenesis associated with common metabolic disorders like diabetes, morbid obesity or metabolic-dysfunction associated steatohepatitis (MASH). Their underlying mechanisms are being studied to elicit new approaches for health impact in early therapeutic or preventive interventions, through translation in proof-of-concept clinical studies.

• A glycolytic metabolite bypasses ‘‘two-hit’’ tumor suppression by BRCA2 
  Kong LR, Gupta K, Wu AJ, Perera D, Ivanyi-Nagy R, Moiz Ahmed SM, Tan TZ, Tan SLW, Fuddin A, Sundaramoorthy E, Shiqing Goh GS, Wong RTX, Costa ASH, Oddy C, Wong H, Patro CP, Kho YS, Huang XZ, Choo J, Shehata M, Lee SC, Goh BC, Frezza C, Pitt JJ, Venkitaraman AR. (2024)
  Cell 187, 2269–2287
  
  
• A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells 
  Najafabadi MG, Gray GK, Kong LR, Gupta K, Perera D, Naylor H, Brugge JS, Venkitaraman A.R.*, Shehata M*. (2023)
  Nature Comm 14(1):5206 (* Joint senior author)|
  
  
• Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia 
  Ferrer M, Mourikis N, Davidson EE, Kleeman SO, Zaccaria M, Habel J, Rubino R, Gao Q, Flint TR, Young L, Connell CM, Lukey MJ, Goncalves MD, White EP, Venkitaraman AR, Janowitz T. (2023)
  Cell Metabolism 35(7):1147-1162.
  
  
• Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities
  Ho TLF, Lee MY, Goh HC, Ng GYN, Lee JJH, Kannan S, Lim YT, Zhao T, Lim EKH, Phua CZJ, Lee YF, Lim RYX, Ng PJH, Yuan J, Chan DKH, Lieske B, Chong CS, Lee KC, Lum J, Cheong WK, Yeoh KG, Tan KK, Sobota RM, Verma CS, Lane DP, Tam WL, Venkitaraman A.R. (2023)
  Nature Comm 14(1):1726.
  
  
• Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library
  Emery, A., Hardwick, B.S., Crooks, A.T., Milech, N., Watt, P.M., Mithra, C., Kumar, V., Giridharan, S., Sadasivam, G., Mathivanan, S., Sudhakar, S., Bairy, S., Bharatham, K., Hurakadli, M.A., Prasad, T.K., Kamariah, N., Muellner, M., Coelho, M., Torrance, C.J., McKenzie, G.J., Venkitaraman, A.R. (2021) 
  Cell Chem Biol 28, 1602-15.
  
  
• A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability
  Tan SLW, Chadha S, Liu Y, Gabasova E, Perera D, Ahmed K, Constantinou S, Renaudin X, Lee M, Aebersold R, Venkitaraman AR. 
  Cell. 2017 169(6):1105-1118.e15.

• Methods for the characterisation of interaction sites on target proteins (WO2013116903)
  The present invention relates to improved and integrated methods for the characterisation of an interaction site on a target protein that modulates the phenotype of a mammalian cell, such as a phenotype other than death and/or reduced growth. Such methods of the present invention include those to identify a target protein modulates such a phenotype of a mammalian cell, and optionally to characterise an interaction site on said target protein. Such identification and characterisation methods are useful in the development of research tools and/or therapeutics, such protein/peptide or small molecule therapeutics. Accordingly, the present invention also relates to methods of: identification of a ligand, such as a small molecule ligand, that binds to such a target protein; and identification a compound being a candidate modulator of said phenotype of a mammalian cell. The invention further relates to peptides or proteins, or fragments, variants and/or derivatives thereof) comprising certain amino acid sequences, nucleic acids encoding such peptides or proteins and uses of such peptides or proteins or of such nucleic acids.
  
  
• A method of screening for modulation of cell signalling pathways (EP3218512)
  A method for the identification of new therapeutic targets and protein interaction sites for use in drug discovery. In particular the invention relates to a method for identifying inhibitors of a cell signalling pathway, the method comprising (1) providing a population of mammalian cells, each mammalian cell having an active cell signalling pathway and comprising: (a) a first heterologous nucleic acid comprising; (i) a nucleotide sequence encoding a first detectable reporter and, (ii) a constitutive regulatory element which is operably linked to the nucleotide sequence; and, (b) a second heterologous nucleic acid comprising: (i) a first nucleotide sequence encoding a repressor molecule, for example an RNA or protein, which inactivates, inhibits or suppresses expression of the first detectable reporter, (ii) a second nucleotide sequence encoding a second detectable reporter; and (iii) a signal-activated regulatory element which is activated by said cell signalling pathway, said signal-activated regulatory element being operably linked to the first and second nucleotide sequences, (2) introducing a library of test compounds into said population of mammalian cells, and; (3) determining the expression of the first and the second detectable reporters in one or more of the population of transfected cells, wherein expression of the first detectable reporter but not the second detectable reporter in a transfected cell is indicative that the test biomolecule expressed by the nucleic acid in the cell inhibits said cell signalling pathway.