Technologies

A novel 19 amino acid peptide, within the ARF tumor suppressor protein, that reduces proliferation of mouse liver tumor cells and increases apoptosis of cells.

• Liver cancer (HCC) is the fifth most common cancer in the world. A deadly disease, liver cancer will kill almost all who contract it within a year. In 1990, the World Health Organization estimated that there were about 430,000 new cases of liver cancer worldwide, and a similar number of patients died as a result of this disease.
• HCC faces a substantial limitation of conventional cancer chemotherapy and radiotherapy. The nonselectivity of the available gene delivery systems also renders cancer gene therapy strategies potentially toxic to normal cell populations.
• The complexity of the relevant gene and lack of clarity regarding its regulatory factors in respect to the gene expression controlling pathway for a specific tumor make it difficult to construct a selective gene therapy.
• Recognizing the need for a targeted cancer therapy the researchers at UIC constructed a unique system, which makes it possible to examine the effect of FoxM1B protein and its relevant cascades for hepatocytecellular carcinomas (HCC).
• They discovered that FoxM1B - forkhead box transcription factor – is essential for development of HCC. Using CRE-LOX technology, the researchers deleted the mouse FoxM1b gene selectively in hepatocytes and then induced liver tumors in these mice using hepatic carcinogens (Alb-Cre Foxm1b fl/fl).
• The researchers found that inhibition of expression of FoxM1B prevented development of mouse HCC in response to chemically induced liver tumors. These mouse genetic studies indicate that FoxM1b is a therapeutic gene to inhibit proliferation and growth of liver tumor cells in mice.
• The UIC investigators also showed that the FoxM1b transcription factor is a novel inhibitory target of the ARF tumor suppressor protein.
• They defined a 19 amino acid peptide within the ARF tumor suppressor protein that was sufficient to inhibit FoxM1b transcriptional activity.
• This ARF peptide was modified by addition of nine D-ARG to facilitate cellular uptake and converted this ARF peptide into a specific inhibitor of FoxM1 function in tissue culture cells. Mice with pre-existing hepatocelllular carcinomas were treated with daily injections of this membrane transducing ARF peptide for duration of 4 or 8 weeks.
• This ARF peptide treatment significantly reduced proliferation of mouse liver tumor cells through the inhibition of FoxM1b activity. Furthermore, the researchers observed a selective 22% increase in apoptosis (programmed cell death) of mouse liver tumor cells without causing apoptosis of the normal surrounding liver tissue.
• The invention provides methods for inhibiting tumor cell proliferation and stimulating tumor cell apoptosis by inhibiting FoxM1B activity with a membrane transducing ARF peptide.