Modeling cancer and macrodrug development
Most tumours have chromosomal abnormalities that occur in the cancer initiating cells. Principal amongst these aberrant chromosomes are chromosomal translocations that are found in leukaemias/lymphomas, sarcomas and epithelial tumours. Our work comprises developing models of chromosomal translocations, using recombination in mouse ES cells that recapitulate these initiating events toolkit to study the molecular consequences and for pre-clinical testing of new drugs, drug combinations or novel macromolecular drugs (macrodrugs). In particular, we are developing antibody fragments that function in the reducing environment within cells to bind their antigen target and prevent protein-protein or protein-nucleic acid interactions. LM02 is an anti-RAS single antibody domain that inhibits the interaction of RAS with the signal transduction effectors such as PI3K, thereby preventing RAS-mediated tumour formation. We are developing methods for delivery of macrodrugs to tumours as well as developing macrodrug mimetics to be used as conventional small molecule drugs. As part of a long term strategy to facilitate personalised medicines, we are developing fast-throughput methods for detecting and cloning aberrations in chromosomes of cancer cells and cancer-initiating cells.
The Section is a member of the UK Drug Discovery Consortium (UKDDC) and the Protein-Protein Interactions Network (PPI-Net)
MTA for fast throughput translocator toolkit plasmids.
Figure 1. Reciprocal chromosomal translocation caused by Cre-loxP recombination in ES-derived cells.
Figure 2. Structure of an anti-RAS antibody fragment bound to RAS
Tanaka, T; Sewell, H; Waters, S; Phillips, S.E.V; Rabbitts, T.H. (2011) Single domain intracellular antibodies from diverse libraries: emphasizing dual functions of LM02 protein interactions using a single VH domain. J. Biol Chem 286: 3707-3716
Tanaka, T; Rabbitts, T.H. (2010) Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth. Oncogene 1-7
Tanaka, T; Rabbitts T H. (2010) Protocol for the selection of single-domain antibody fragments by third generation intracellular antibody capture. Nature Protocols 2; 67-92
Perez-Martinez, D; Tanaka, T; Rabbitts, T.H. (2010) Intracellular antibodies and cancer: new technologies offer therapeutic opportunities. Bioessays 32: 589-598
McCormack MP, Young LF, Vasudevan S, de Graaf CA, Codrington R, Rabbitts TH, Jane SM, Curtis DJ. (2010). The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal. Science, Feb 12, 327 (5967); 879-83
McCaughan, F; Pole, J.C.M; Bankier, A.T; Konfortov, B.A; Carroll, B; Falzon, M; Rabbitts, T.H; George, P.J; Dear, P.H; Rabbitts, P.H. (2010) Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer. Am J Respir Crit Care Med, 182: 83-91
Rabbitts, T.H. (2009) Commonality but diversity in cancer gene fusions Cell 137, 391-395
Tanaka, T., Williams, R., Rabbitts, T.H. (2007) Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS EMBO J 26, 3250-3259
Daser, A., Thangavelu, M., Pannell, R., Forster, A., Sparrow, L., Chung, G., Dear, P.H. & Rabbitts T.H. (2006) Interrogation of genomes by Molecular Copy-number Counting (MCC) Nature Methods 3, 447-453
Forster, A., Pannell, R., Drynan, L.F., Codrington, R., Daser, A., Metzler, M., Lobato, M.N. & Rabbitts T.H. (2005) The invertor knock-in conditional translocation mimic Nature Methods 2, 27-30
Forster, A., Pannell, R., Drynan, L. F., McCormack, M.M., Collins, E.C., Daser, A. & Rabbitts, T.H. (2003) Engineering de novo reciprocal chromosomal translocations associated with Mll to replicate primary events of human cancer. Cancer Cell 3, 449-458