Apotherapy: CD40 ligand-based modalities for the treatment of cancer.
Cancer is a major disease which is responsible for approximately 23% of all deaths in the European Union. Epithelial tumours, such as those of the ovary, lung and oesophagus, have particularly poor prognosis, with only a minority of patients achieving a 5 year survival. Conventional treatments, including chemotherapy and radiotherapy, have limited efficacy and frequently cause severe side effects in the patients.
The Apotherapy project brings together expertise from academic and biotechnology sectors across 7 European countries with the aim to develop and validate novel anti-cancer agents with wide therapeutic index and minimal side-effects. The focal point of our research is the utilisation of combined approaches which attack the tumour cell at multiple levels, achieving maximal apoptosis while limiting the risk of drug resistance. These approaches involve the efficient delivery of a pro-apoptotic molecule to cancer cells in combination with inhibitors of anti-apoptotic signal transduction pathways.
Specifically, the project will formulate therapeutic strategies which exploit the ability of CD40 ligand (CD40L), a TNF family member, to reduce proliferation, promote apoptosis and activate anti-tumor immune responses selectively in cancer cells. Apotherapy will develop state-of-the-art vehicles for the efficient delivery of CD40L to cancer cells, such as CD40L-encapsulated liposome formulations and recombinant adenoviruses expressing CD40L and examine their in vitro and in vivo effects on tumour cell growth and metastasis.
Apoptosis induced by CD40 engagement is dramatically augmented in the presence of inhibitors of the phosphoinositide 3-kinase (PI3 kinase) pathway which is frequently found activated in human tumours. The Apotherapy project will expand on the development of novel PI3 kinase antagonists and evaluate their in vitro and in vivo capacity to kill tumour cells and to amplify the CD40L-mediated effects on carcinoma cell growth, angiogenesis and metastasis.
The Apotherapy project is expected to lead to the development of novel anti-cancer strategies which will be directly applicable to the clinic for the benefit of cancer sufferers. The strong focus on translational research will translate R&D results into tangible benefits for health, science and economy in Europe.