LICR Breast & Prostate Cancer Initiative Meeting Report
Zurich, June 21 & 22
Prof. A. Munro Neville gathered together a group of LICR investigators, Affiliates and other close collaborators for a Breast & Prostate Cancer Initiative (BPCI) meeting at the University Hospital Zurich, Switzerland. The meeting had three main themes: properties of normal and neoplastic breast cells; the role of the stroma in tumor growth and cancer metastasis, and; clinical research activities leading to the development of novel diagnostics and therapies.
Several speakers described studies that distinguish the properties of normal and neoplastic breast cells and present new potential targets for drug therapy. The London group, headed by LICR Affiliate Dr. Parmjit Jat (Institute of Neurology), presented a comprehensive gene expression profiling study of normal and malignant breast epithelium, combining massively parallel signature sequencing (MPSS) and microarray analysis, in which many genes that are differentially expressed in malignant cells were identified. Several of these genes represent potential therapeutic targets, including the secreted protein Periostin that also appears to be a marker for poor prognosis. A common feature of breast cancer cells is the overexpression of the epidermal growth factor receptor erbB2 (HER2/neu). Dr. Ana Paula Silva (Sao Paulo Branch) described the identification of three genes that are induced in breast cancer cell lines overexpressing erbB2, and that were found to be overexpressed in breast tumors. She also presented new insights to the function of ADAM23, a gene shown by the group to be frequently silenced in advanced stages of breast cancer by DNA methylation, correlating with a risk of developing distant metastases and overall survival. Dr. Giuseppe Pelicci (European Institute of Oncology) presented an analysis of normal and transformed stem and progenitor cells, which were isolated from mouse breast and propagated in suspension as ‘mammospheres.’
Tumors are supported by connective tissue of non-proliferating stromal cells, and alterations in these cells play an important role in tumor growth, invasion and metastasis. LICR Affiliate Dr. Arne Östman (Karolinska Institute) presented a transcriptomic study of cancer-associated fibroblasts isolated from stroma of different tumor types, which uncovered tumor-type specific gene expression signatures that have therapeutic and prognostic potential. Dr. Ulf Eriksson (Stockholm Branch) revealed novel implications of the stromal platelet-derived growth factors (PDGFs) C and D, originally discovered by his group, in progression of human tumors. Dr. Aris Moustakis (Uppsala Branch) discussed mechanisms that account for the contrasting roles of transforming growth factor beta (TGFβ) in cancer, which is a stromal factor that acts as a tumor suppressor in normal tissues, but is oncogenic in malignant tumors. TGFβ induces ’epithelial to mesenchymal’ transition (EMT), which is known to play a central role in metastasis. Affiliate Dr. Serhiy Souchelnytskyi (Karolinska Institute) followed this by describing changes in protein expression and phosphorylation induced by TGFin breast cancer cell lines as detected by mass spectrometry.
Dr. Otavia Caballero (New York Branch) described research to identify cancer testis (CT) antigens that may be of value as targets for therapeutic breast cancer vaccines. She has conducted a systematic analysis of the expression of the more than 90 CT antigens described to date in both normal and neoplastic tissues. Dr. Caballero’s studies have identified several CT antigens that are strongly expressed in estrogen receptor (ER)-negative poor prognosis breast cancers. NY-BR-1, another potential cancer target that was discovered by LICR Affiliates Dr. Dirk Jäger (University Clinic Heidelberg) and Alex Knuth (University Hospital Zurich) is undergoing preclinical analyses. The LICR Office of Clinical Trials Management is preparing the regulatory documentation required to initiate a Phase I clinical trial of a vaccine based on NY-BR-1.
LICR believes that therapeutic cancer vaccines may be applied optimally as an adjuvant therapy, following removal of the tumor, to prevent tumor regrowth and metastasis. Dr Martin Slade (Imperial College London) addressed the issue of detecting breast cancer patients with minimal residual disease after initial therapy and with no evidence of metastases as shown by conventional methods. Several approaches to identify micrometastases have been explored, including detection in bone marrow aspirates and identification of circulating tumour cells (CTC). Future studies will assess the functional properties of bone marrow tumour cells and CTC with regard to their potential for subsequent tumour development at various metastatic sites.
Finally, Professor Sir Gordon McVie (European Institute of Oncology) and Dr. Serena di Cosimo (Vall d’Hebron University Hospital Research Institute) outlined current clinical and diagnostic activities, including clinical trials of targeted therapies, being undertaken in Europe. The facilities and various partnerships, together with the tissue banks, offer a rich source of material and expertise for future interaction with the BPCI.
The BPCI meeting brought together 22 participants from five Branches (London, New York, São Paulo, Stockholm, Uppsala) and seven Affiliates or collaborating institutions (European Institute of Oncology, Milan, Italy; University Clinic Heidelberg, Heidelberg, Germany; Imperial College London, London, UK; Institute of Neurology, London, UK; Karolinska Institute, Stockholm, Sweden; University Hospital Zurich, Zurich, Switzerland, and; Vall d’Hebron University Hospital Research Institute, Barcelona, Spain).