Grant: Project Grant

CX-5461 is an interesting anti-cancer drug candidate. It was originally developed as an agent that inhibits a protein that is important in producing RNA, the material in cells responsible for producing proteins. Since that time it has been shown to act as a DNA poison and an agent that promotes a unique form of cancer cell death called apoptosis. Thus, like many anti-cancer agents, CX5461 acts through multiple mechanisms. Although aqueous CX5461 formulations can be made for intravenous use, none are ideal because the agent is very water insoluble this limits its usability. Also when CX5461 is given to patients it causes severe skin toxicities and this also limits its potential to help patients. The applicant's lab discovered that CX-5461 forms a complex with certain metals; specifically zinc and copper. This interaction between CX-5461 and the metal has allowed the applicant to formulate CX-5461 using liposomes. Liposomes are small spherical structures formed from lipids (fats) when they are mixed with water. The applicant wants to develop a liposomal CX5461 formulation for use in patients with pancreatic cancer patients. The research challenges are many. First the formulation needs to be designed for optimal use to treat cancer growing in the pancreas and elsewhere- sites where the pancreatic cancer has spread. The formulation must be tolerated better then the currently used formulation, i.e. the skin toxicity of the liposomal formulation must be reduced. Since liposomes are being used and can control how CX5461 is delivered over time after administration, the ideal liposome lipid composition needs to be identified. It is important to show that the liposomal formulation of CX5461 does not adversely affect the actions of other drugs currently used to treat pancreatic cancer. Finally, the formulation needs to be made in manner suitable for manufacturing for use in humans. The research in this application will address all these issues.