Suppression of prostate cancer using a targeted clostridial neurotoxin
The present invention relates to a method for suppressing or treating cancer, in particular to a method for suppressing or treating one or more of colorectal cancer, breast cancer, prostate cancer and/or lung cancer. The therapy employs use of a non-cytotoxic protease, which is targeted to a growth hormone-secreting cell such as to a pituitary cell. When so delivered, the protease is internalised and inhibits secretion/transmission of growth hormone from said cell. The present invention also relates to polypeptides and nucleic acids for use in said methods.
1. A method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a polypeptide comprising an amino acid sequence comprising:
a) a non-cytotoxic protease comprising a clostridial neurotoxin endopeptidase capable of cleaving a protein of the exocytic fusion apparatus in a pituitary cell;
b) a targeting moiety that is capable of binding to a growth hormone-releasing hormone (GHRH) receptor on the pituitary cell; and
c) a translocation domain comprising a clostridial neurotoxin translocation domain capable of translocating the protease from within the endosome of the pituitary cell, across the endosomal membrane, and into the cytosol;
wherein:
the pituitary cell is a normal, non-diseased, noncancerous cell;
the method reduces secretion of growth hormone from the cell;
the cancer is prostate cancer; and
the amino acid sequence is effective at treating prostate cancer.
2. The method of claim 1 , wherein the targeting moiety is a growth hormone-releasing hormone (GHRH), truncation, or peptide analogue thereof.
3. The method of claim 1 , wherein the amino acid sequence has at least 90% sequence identity to any one of SEQ ID NO: 36, 37, or 38.
4. The method of claim 1 , wherein the amino acid sequence has at least 95% sequence identity to any one of SEQ ID NO: 36, 37, or 38.
5. The method of claim 1 , wherein the amino acid sequence has at least 98% sequence identity to any one of SEQ ID NO: 36, 37, or 38.
6. The method of claim 1 , wherein the amino acid sequence has at least 95% sequence identity to SEQ ID NO: 36.
7. The method of claim 1 , wherein the targeting moiety comprises SEQ ID NO: 94.
8. The method of claim 1 , wherein the amino acid sequence is any one of SEQ ID NO: 36, 37, or 38.
9. The method of claim 1 , wherein the targeting moiety has the amino acid sequence of any one of SEQ ID NOs: 88, 91, 92, or 94.
10. The method of claim 1 , wherein the targeting moiety has at least 90% sequence identity to any one of SEQ ID NOs: 88, 91, 92, or 94.
11. The method of claim 1 , wherein the targeting moiety has at least 95% sequence identity to any one of SEQ ID NOs: 88, 91, 92, or 94.
12. The method of claim 1 , wherein the targeting moiety has at least 90% sequence identity to any one of SEQ ID NOs: 91, 92, or 94.
13. The method of claim 1 , wherein the targeting moiety has at least 95% sequence identity to any one of SEQ ID NOs: 91, 92, or 94.
14. The method of claim 1 , wherein the targeting moiety has the amino acid sequence of any one of SEQ ID NOs: 91, 92, or 94.