Abstract

Current oncology therapies face difficulties in opposing the regenerative properties of cancer; as a result, some cancers have a very low life expectancy and many cancers have a significant probability of recurrence. At the cellular level, this is largely because some cancer cells evade therapy and then regenerate the tumour. At the molecular level, they do so by switching molecular growth mechanisms. When a drug designed to disrupt established growth mechanisms is applied, they switch over to operating an alternative mechanism (the Hes3 Signalling Axis), thus continuing disease progression. Operation of the alternative mechanism confers stem cell-like qualities that may help the regeneration of the tumour. At the heart of this alternative mechanism is the gene Hes3, a transcription factor that is found to be expressed in regenerating tissue and multiple cancers (including gliomas, pancreatic and lung). In multiple types of cancer, Hes3 expression correlates with reduced life expectancy. Having identified this mechanism, we are now validating the efficacy of two types of treatment at the pre-clinical stage: 1. A Hes3 siRNA that directly targets Hes3 and. 2. A series of FDA -approved small molecule drugs we aim to repurpose in oncology that in vitro specifically kill glioma cells only when they operate the Hes3 signalling axis. Optimal delivery of these treatments in the context of gliomas (to start with) is critical to the success of this new therapeutic strategy.