TCF responsive element
AssigneeML Laboratories PLC
InventorsLawrence S. Young, Kai S. Lipinski, Christopher J. Wrighton
Life of this patent
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Abstract
Disclosed are DNA elements and constructs useful for obtaining tumour-selective gene expression in tumours having a mutated β-catenin/APC pathway. In particular, the use of these constructs to express genes encoding therapeutic proteins in colorectal cancer cells is described. The constructs comprise multiple repeats of a TCF-binding element operably linked to a promoter. By means of such a construct, tumour cell-specific expression of a prodrug-converting enzyme such as nitroreductase may be achieved. Coupled with systemic administration of a suitable prodrug, such as CB1954, selective killing of such tumour cells can be demonstrated.
Claims29
A nucleic acid construct comprising:
- 1) a V-cell factor (TCF) response element comprising:
- at least one TCF binding element having the sequence CTTTGNN wherein N is A or T;
- and
- an operably linked promoter;
- and
- 2) an expressible gene that is useful for the treatment of a cancer that is characterised by deregulation of Writ pathway signalling;
- wherein the expressible gene is operably linked to the TCF response element which enables inducible expression of the gene.
A nucleic acid construct comprising:
- 1) a TCF response element comprising:
- at least 5 TCF binding elements having the sequence CTTTGNN wherein N is A or T;
- and
- an operably linked promoter;
- and
- 2) an expressible gene that is useful for the treatment of a cancer that is characterised by deregulation of Wnt pathway signalling;
- wherein the expressible gene is operably linked to the TCF response element which enables inducible expression of the gene.
A nucleic acid construct comprising:
- 1) a TCF response element comprising:
- at least two TCF binding elements having the sequence CTTTGNN wherein N is A or T;
- and
- an operably linked promoter;
- and
- 2) an expressible gene that is useful for the treatment of a cancer that is characterised by deregulation of Wnt pathway signalling;
- wherein die expressible gene is operably linked to the TCF response element which enables inducible expression of the gene, and wherein the TCF binding elements are separated from each other by between 3 and 20 nucleotides.
A nucleic acid construct comprising:
- 1) a TOF response element comprising:
- at least one TCF binding element having the sequence CTTTGNN wherein N is A or T;
- and
- an operably linked promoter;
- and
- 2) an expressible gene that is useful for the treatment of a cancer that is characterised by deregulation of Wnt pathway signalling;
- wherein the expressible gene is operably linked to the TUE response element which enables inducible expression of the, and wherein the TCF binding element closest to the promoter is between 140 and 10 nucleotides from the TATA box of the promoter.
Dependencies are inferred from the claim text.