Dr Teresa Coughlan, University of Nottingham (£48,199)
Targeting gene therapy to primary bone cancers using novel delivery of RNA interference by attenuated bacteria.
Osteosarcoma (OS) is the most common form of primary bone cancer. Although its incidence is rare, children and adolescents are particularly affected and this sarcoma tends to have a poor prognosis, often not responding well to current treatment options. Prognoses have remained unchanged for decades and the potential for novel improvements in therapy is enormous.
Recent developments have arisen through advances in the elucidation of molecular pathways involved in OS. Various types of pharmacological inhibitors are now in development, which target specific molecules that are dysregulated in these tumours. Gene therapy approaches are also being studied.
One of the problems with potential therapies that work well in vitro, including gene therapy, is delivery to the tumour- particularly as many targets for therapy are also present in normal tissue, where inhibition would be undesirable. Furthermore, as a poorly vascularised region, penetrance of tumour by systemically administered drugs is poor.
We have developed an attenuated strain of the bacteria Salmonella typhimurium that preferentially colonizes tumours and can be modified to express molecules that kill tumour cells (1). Similar bacteria have been used in previous studies, including a recent report targeting osteosarcoma (2), and these bacteria have already been used safely in clinical trials.
We propose to further improve the therapeutic potential of our bacteria, by modifying them to express RNA interference plasmids targeting genes that are dysregulated in OS, such as the proven therapeutic target, insulin-like growth factor-1 receptor (IGF1R). This approach should also benefit other primary bone and non-bone cancers.
