UCL Cancer Institute

Cancer Research UK Drug-DNA Interactions Research Group


Group Leaders: Professor John Hartley and Professor Daniel Hochhauser




The Cancer Research UK Drug-DNA Interactions Research Group was established in 1995 with the aim of contributing to the development of new and improved cancer therapies based on DNA as a target.


Research

The activities of the group are centred on the following areas.

The development and exploitation of methods to study drug-DNA interactions, and their repair, at the genome, gene, sub-gene and single nucleotide level in naked DNA and intact cells (both in vitro and in clinical samples).

To use the information derived from experiments in biological systems to assist in the design and evaluation of novel DNA interacting drugs, in particular, DNA interstrand cross-linking agents, and DNA sequence specific agents as potential modulators of gene expression.

To define the major repair pathways for drug-DNA adducts and to explore the relationship between different types of drug-induced DNA damage, the efficiency of repair of these lesions, and biological response.

To determine the molecular basis of inherent sensitivity of some tumour types to DNA damaging agents and the molecular basis of clinical acquired resistance to DNA damaging drugs in order to develop strategies to overcome or circumvent this resistance.

Footprint

Fig 1   Single cell gel electrophoresis (comet) assay images of irradiated human lymphocytes either before (a) or after (b) treatment with a DNA cross-linking drug.
Fig 2   DNase 1 footprinting showing the sequence selective interaction of a DNA minor groove binding agent.



EGFR

Fig 3   Cellular staining of EGFR showing relocation from the cytoplasm (left) to the nucleus (right) following DNA damage.



DNA model



Fig 4   Molecular model showing 2:1 binding of sequence selective non-covalent DNA binding agents (blue) in the minor groove of DNA.
















 

Selected Publications


Hochhauser, D., Meyer, T., Spanswick, V.J., Wu, J., Clingen, P.H., Cobb, M., Gumbrell, L., Begent, R.H., Hartley, J.A., and Jodrell, D.: Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. Clinical Cancer Res., 15, 2140-47, 2009.

Boone, J.J.M., Bhosle, J., Tilby, M.J., Hartley, J.A., and Hochhauser, D.: Involvement of the Her2 pathway in repair of DNA damage produced by chemotherapeutic agents. Mol. Cancer Therapeutics., 8, 3015-23, 2009.

Middleton, M.R., Knox, R., Cattell, E., Oppermann, U., Midgley, R., Ali, R., Auton, T., Anderson, D., Sarker, D., Judson, I., Osawa, T., Spanswick, V.J., Davies, S., Hartley, J.A., and Kerr, D.J.: Quinone oxidoreductase-2 mediated prodrug cancer therapy. Science Translational Medicine, 2, 40ra50, 2010.

Hartley, J.A., Hamaguchi, A., Coffils M., Martin, C., Suggitt, M., Chen, Z., Gregson, S.J., Masterson, L.A., Tiberghien, A.C., Hartley, J.M., Pepper, C.J., Lin, T.T., Fegan, C., Thurston, D.E., and Howard, P.H.: SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer pro-drug that cross-links DNA and exerts highly potent antitumor activity. Cancer Res., 70, 6849-58, 2010.

Ledermann, J.A., Gabra, H., Jayson, G.C., Spanswick, V.J., Rustin, G.J.S., Jitlal, M., James, L.E., and Hartley, J.A.: Inhibition of carboplatin-induced DNA interstrand crosslink repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer. Clinical Cancer Res., 16, 4899-905, 2010.

Liccardi, G., Hartley, J.A., and Hochhauser D.: EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res., 71, 1103-14, 2011.

Puzanov, I., Lee, W., Chen, A.P., Calcutt, M.W., Hachey, D.L., Vermeulen, W.L., Spanswick, V.J., Liao, C-Y., Hartley, J.A., Berlin, J.D., and Rothenberg, M.L.: Phase I, pharmacokinetic and pharmacodynamic study of SJG-136, a novel DNA sequence selective minor groove cross-linking agent, in advanced solid tumors. Clinical Cancer Res., 17, 3794-802, 2011.

Hartley, J.A., Hamaguchi, A., Suggitt, M., Gregson, S.J., Thurston, D.E., and Howard, P.W.: DNA interstrand cross-linking and in vivo antitumour activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057. Investigational New Drugs, in press, 2011.

Osawa, T., Davies, D and Hartley, J.A.: Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells. Cell Death and Disease, 2, e187, 2011.

Wang, AT, Sengerova, B, Cattell, E, Inagawa, T, Hartley, JM, Kiakos, K, Burgess-Brown, NA, Swift, LP, Enzlin, JH, Schofield, CJ, Gileadi, O, Hartley, JA and McHugh, PJ. Human SNM1A collaborates with XPF-ERCC1 to initiate DNA interstrand cross-link repair. Genes and Development, 25, 1859-1870, 2011.