Making Herceptin-resistant tumours Herceptin responsive: adapting new therapeutic potential from Head and Neck Cancer research to improve breast cancer outcomes

Our team investigates the prediction and response of Head and Neck cancer patients to a monoclonal antibody therapy called Cetuximab. Cetuximab recognises ErbB1 (Her 1/EGFR) protein when it is present on the surface of cancer cells, however it is not effective in all patients. We have discovered a way to make Cetuximab effective for a larger number of patients. Moreover, we found this approach also works for Herceptin, the monoclonal antibody which recognises ErbB2 (Her2) protein on breast cancer cells. We found that by moving ErbB1(Her1) and/or ErbB2 (Her2) receptors to the tumour cell surface, they are able to interact with the antibody therapies and generate a much better immune response, which kills even normally resistant cancer cells. Crucially, there are drugs that have been in clinical use for thirty years that can do just this. These drugs (Stemetil, Haloperidol and CPZ) are commonly used as anti-psychotics and anti-nausea treatments, and have been used in advanced cancer palliative care. We want to determine which of these compounds best promotes Herceptin-mediated tumour cell killing in HER2 cells in order to move forward to breast cancer patient trials. We also found that we could get enough ErbB1 (Her1) and ErbB2 (Her2) onto the surface of triple negative breast cancer cells to allow Herceptin and Cetuximab mediated killing. We are starting clinical trials in Head and Neck SCC patients and this proposal covers the work necessary to run a similar trial in breast cancer patients with Her2 positive tumours or triple negative tumours.