Targeting cancer stem cells in breast tumours ex vivo

We have discovered a method to selectively eliminate the tumour-forming potential of breast cancers by destroying the so-called cancer stem cells, thought to be responsible for the spread of the disease in breast cancer patients. These experiments were performed in a laboratory setting using cancer cells that had been propagated for long periods outside of the body. Thus despite the striking anti-cancer effects observed, there remains the key question of whether these findings have direct clinical relevance for breast cancer patients. We aim to address this by testing our putative therapeutic strategy directly on breast tumour tissues.

We have recently obtained ethical consent to acquire fresh tumour biopsy tissues from patients attending a regional Breast Clinic. These tissues will be used to test the experimental therapy over a much shorter time frame in the laboratory, in order to maintain the integrity and therefore the clinical relevance of the human tissues. The therapeutic approach involves suppression of the gene for cFLIP combined with the addition of the anti-cancer agent TRAIL. This induces a highly selective apoptotic response in the tumour-initiating cell population. We will initially use a genetic approach involving lentiviral vectors conditionally expressing shRNA to specifically suppress cFLIP in the primary tumour samples in culture, followed by the addition of TRAIL to the culture medium. We will assess the cytotoxic effects on both cancer stem cells and the tumour as a whole, and will correlate any responses to the particular subtypes of breast cancer. The student will receive comprehensive training in a broad spectrum of techniques including cell culture of human tissues and established cell lines, transplantation models, histology and cancer stem cell biology. The project will be co-supervised by an experienced post-doc at the bench, working in a team atmosphere from the start to optimise and develop the primary culture and lentiviral systems. This study represents a key proof-of-principle translational step towards testing this therapeutic strategy in clinical trials.