Professor Nigel Bundred - Research interests
Professor Bundreds current research programme is concentrated on two main areas: breast cancer, and Parathyroid Hormone related protein/hypercalcaemia of malignancy. Currently has a team of 2 research registrars, 2 postdoctoral assistants and 2 technicians working on various current laboratory research areas. In addition 3 ½ research nurses and 1 graduate research worker are working on various clinical trials on studies for which he has obtained funding. In total nine MD theses and 1 PhD have been awarded under his supervision to date.
Active research areas encompass breast cancer prevention, mechanisms of bone metastasis, angiogenesis, stem cell (non-adherent) culture of DCIS and invasive breast cancer.
Carcinoma in Situ (DCIS)
DCIS constitutes 30% of all screen detected breast cancer. Professor Bundred has developed an athymic nude mouse model in which human DCIS is implanted as xenografts and survives up to two months, in collaboration with Professor Chris Potten, who was previously at the Paterson Institute for Cancer Research
In xenografts removed sequentially at 14, 28 and 56 days proliferation and steroid receptor expression were measured. Oestrogen Receptor Negative Comedo DCIS was not stimulated by oestrogen nor inhibited by the pure antioestrogens (ICI 182780). In contrast, papillary or cribriform (steroid receptor positive) DCIS was stimulated to proliferate by oestrogen implants (paper published in J Natl Cancer Inst). His group since followed up these studies by examining whether monoclonal antibodies to the CerbB2 oncogene or Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition prevent DCIS growth. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition with Iressa prevented epithelial proliferation and induced apoptosis both in normal breast and DCIS xenografts implanted into nude mice whereas monoclonal antibody to CerbB2 oncoprotein had no such effects. In addition, Iressa inhibited downstream signalling pathways including MAPkinase and phosphorylation of the EGFR. Other studies using breast cancer cell lines expressing EGFR and CerbB2 have demonstrated that blocking the EGFR also inhibits phosphorylation of the CerbB2 oncoprotein and downstream signalling.
RAS Farnesyl Transferase Inhibition research has won national and international recognition with the award of the Patey Prize to Mr Kai Chan, Research Registrar at the Surgical Research Society in December 1999 and with publication in prestigious American Journals (J National Cancer Institute and Cancer Research). A follow-up paper on the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor work has been published in Cancer Research. The major thrust of the research is currently in the area of pre-invasive malignancy in breast cancer and the factors that promote conversion of DCIS to an invasive malignancy.
More recently professor Bundred has identified stem cells from DCIS lesions and demonstrated growth inhibition of non-adherent stem like cells by NOTCH and epidermal growth factor receptor inhibition.
He has pioneered the developed of IAP kinase development of preoperative studies in ductal carcinoma in situ and a recent study has shown that an aromatase inhibitor (Exemestane) significantly inhibits proliferation in oestrogen receptor positive DCIS. His group has currently received Ethical Approval and have initiated the trial of a HER1/2 small molecule inhibitor, Lapatinib, in DCIS preoperatively. This trial will investigate the mechanism of action of Lapatinib and look for potential markers of response.
Treatment of HER2 Positive Breast Cancer
Professor Bundred has demonstrated that HER2 positive treatment reduces stem cell population in breast cancer cell lines and in ductal carcinoma in situ (DCIS). He has initiated a clinical trial EPHOS-B which will study the role of Lapatinib and Herceptin on proliferation and apoptosis at 11 days in HER2 positive breast cancers compared to control (untreated) cancers. The aim of this study is to determine whether either agent inhibits proliferation or increases apoptosis and what biomarkers can be identified for treatment response. Additionally, he has ongoing research looking at the role of IL-8 and the IL-8 receptor (CXCR1/2) in HER2 positive cancer stem cell renewal and we are investigating whether inhibitors of the CXCR1/2 receptor prevent HER2 positive breast cancer growth, both alone and in combination with anti-HER2 therapy.
Cancer Associated Fibroblasts
Together with Professor Landberg, he is investigating whether we can switch off the activation of fibroblasts seen in breast cancer using a number of novel agents. Importantly, we are asking whether inhibiting the fibroblast may have effects on cancer stem cell renewal and breast cancer growth.