New Approaches in Developing Gene Transfer Vectors for the Therapy of Solid Tumours

Of diagnosed cancers, 90% are solid tumours. A high percentages (up to 75%) of these cancers are diagnosed at a late stage when available conventional therapies are ineffective. Gene therapy is a new modelity that has shown promises in preclinical experiments, but the theaputic potential has yet to be realised in the clinic. Recent understanding of tumour biology demonstrated the difficult and disappointing nature with conventional therapies. As the tumour masses enlarge, the vasculature becomes inadequate to meet the demands of the fast growing tumour cells. Consequently, angiogenesis and hypoxia occur, which in turn induced pathological changes in the tumour, ie.: the emergence of hypoxic and necrotic regions, the heterogeneity of tumour cell population, and the anaerobic metabolism. All these played a fundamental role in the treatment failure. The unique patho-physiology of solid tumour can, in fact, be turned to an advantage as hypoxia and necrosis provided a haven for certain species of anaerobes. Amongst them, clostridia were found to have the ability of spontaneous colonization, apparent selectivity and considerable oncolysis. Clinical trials used wild-type clostridia for the treatment of solid tumours, such as malignant glioma had showed efficacy and safety 50 years ago, but the life span of the patients did not extend due to incomplete tumour lysis, allowing regrowth and reoccurrence. This is the result of the well-nourished proliferative rim of the tumour that is not conducive to growth of oxygen-sensitive clostridia. The advance of recombinant DNA technology reignited the field, enabling genetic improvement of clostridia's innate oncolytic capability. This presentation will summarise the progress in the use of clostridia for oncolytic cancer therapy as well as rationales and strategies in the development of clostridia-based gene delivery system using gene therapy technologies. It is expected that new clostridia-based gene therapy vectors will be of great use for the therapy of primary solid tumours as well as metastasis, the fatal cause of most cancer death.Griffith Health, School of Medical ScienceNo Full Tex