Cells have developed a sophisticated approach to the initial sensing and subsequent repair of DNA damage to preserve genetic stability. The objective of my clinico-translational laboratory is to understand the effect of the tumour microenvironment on the ATM-p53-53BP1 DNA damage signaling pathway and DNA double-strand break (DNA-dsb) repair. Our studies suggest that hypoxic tumour cells can have decreased DNA-dsb repair (e.g., decreased homologous recombination) and an aggressive ''mutator'' phenotype. We are therefore tracking DNA damage responses and repair within normal and tumour tissues to develop novel diagnostics and molecular-targeted therapies.

We interrogate protein-protein interactions during DNA-dsb repair and cell-cycle checkpoints using: siRNA knockdowns, DNA-rejoining assays (comet and CFGE assays), chromatin immunoprecipitation (ChIP), biochemical fractionation, fluorescently-tagged proteins and quantitative confocal microscopy with UV-microbeams (www.sttarr.ca).

1. Cancer therapy and DNA repair: Mutations in DNA repair and tumour suppressor genes are common in many human cancers. We are interested in certain mutated DNA damage proteins (i.e., MTp53, ATM, 53BP1) and DNA damage cell cycle checkpoints. This can lead to therapy resistance. We are tracking the sub-cellular location and function of ATM-dependent protein phosphoforms in response to DNA breaks and evaluating new therapies that target MTp53.



2. Hypoxia, DNA repair and prostate cancer: Many prostate cancer patients die each year solely from the failure of radical radiotherapy to control the primary tumour. We are interested in developing genomic (SNP, CGH) and proteomic (serum, plasma or urine) biomarkers to predict cancer therapy cure and toxicity. This includes the assessment of tissue microarrays (TMAs) for novel protein expression in patients who fail therapy. For example, we are investigating the role of hypoxia as a negative prognostic factor in prostate and other cancers. We believe that novel cancer therapies can target these resistant hypoxic cells by taking advantage of DNA repair defects. We therefore hope to select the most effective treatment for individual patients based on individual biology. For more information, see: http://www.radiationatpmh.com/body.php?id=165.

• Ishkanian AS, Mallof CS, Ho J, Meng A, Albert M, Syed A, van der Kwast T, Milosevic M, Yoshimoto M, Squire JA, Lam W and Bristow RG. High-resolution array CGH identifies novel regions of genomic alteration in intermediate-risk prostate cancer. Prostate, 69(10): 1091-100, 2009. (Senior Responsible Author)

• Chan N, Kortzinky M, Zhao H, Bindra R, Glazer PM, Powell S, Wouters B, Bristow R. Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res 68(2): 605-14, 2008. (Senior Responsible Author)

• Bristow R, Hill RP. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8(3):180-92, 2008. (Principal Author)

• Cuddihy AR, Jalali F, Coackley C, Bristow R. WTp53 induction does not over-ride MTp53 chemo- and radioresistance due to gain of function in lung cancer cells. Mol Cancer Ther 7(4):980-92, 2008. (Senior Responsible Author)

Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR)
Radiation Medicine Program - Bristow Lab
The Tumour Microenvironment Group