Use of peptides that block metadherin-SND1 interaction as treatment for cancer
The present disclosure related in general to methods of treating cancer by interfering with the interaction of metadherin with Staphylococcal nuclease domain-containing 1 (SND1) using peptides or other compounds that inhibit the binding of SND1 with metadherin and inhibit the activity of the MTDH-SND1 complex in tumor cells.
1. A method for reducing the progression of tumor growth or inhibiting metastasis in a subject having cancer comprising administering to the subject an inhibitor that disrupts the interaction between metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1), wherein the inhibitor is a peptide or a fusion protein comprising the peptide linked to one or more polypeptides not generally recognized to be part of the sequence of MTDH, wherein the peptide comprises the amino acid sequence of DWNAPAEEWGN (SEQ ID NO: 5) or a variant thereof, wherein the variant has one or two mutations at positions selected from the group consisting of D393, N395, A396, PAE397-399, E399, E400, and N403, wherein the amino acid positions are based on SEQ ID NO: 1, and wherein the peptide is about 11 to about 22 amino acids long.
2. A method of treating cancer in a subject having cancer comprising administering to the subject an inhibitor that disrupts the interaction between MTDH and SND1, wherein the inhibitor is a peptide or a fusion protein comprising the peptide linked to one or more polypeptides not generally recognized to be part of the sequence of MTDH, wherein the peptide comprises the amino acid sequence of DWNAPAEEWGN (SEQ ID NO: 5) or a variant thereof, wherein the variant has one or two mutations at positions selected from the group consisting of D393, N395, A396, PAE397-399, E399, E400, and N403, wherein the amino acid positions are based on SEQ ID NO: 1, and wherein the peptide is about 11 to about 22 amino acids long.
3. The method of claim 1 , wherein the inhibitor binds a region of human SND1 within residues 16-339 of SND1 (SEQ ID NO: 2).
4. The method of claim 1 , wherein the inhibitor is a peptide of about 11 to about 22 amino acids long, and wherein the peptide is selected from the group consisting of i) a peptide within residues 364-582 of SEQ ID NO: 1, ii) a peptide within residues 364-407 of SEQ ID NO: 1, iii) a peptide comprising residues 386-407 of SEQ ID NO: 1, iv) a peptide comprising residues 393-403 of SEQ ID NO: 1; and v) a peptide comprising residues 390-403 of SEQ ID NO: 1.
5. The method of claim 1 , wherein the cancer is breast cancer or prostate cancer.
6. The method of claim 1 , wherein the subject is a human subject.
7. The method of claim 1 , wherein the peptide is part of a fusion protein, and wherein the peptide is fused to an Fc domain.
8. A method of disrupting the interaction between MTDH and SND1 interaction in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an inhibitor that disrupts the interaction between metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) and a pharmaceutically acceptable carrier, excipient or diluent, wherein the inhibitor is a peptide or a fusion protein comprising the peptide linked to one or more polypeptides not generally recognized to be part of the sequence of MTDH, wherein the peptide comprises the amino acid sequence of DWNAPAEEWGN (SEQ ID NO: 5) or a variant thereof, wherein the variant has one or two mutations at positions selected from the group consisting of D393, N395, A396, PAE397-399, E399, E400, and N403, wherein the amino acid positions are based on SEQ ID NO: 1, and wherein the peptide is about 11 to about 22 amino acids long.
9. The method of claim 1 , wherein the peptide is conjugated to or in admixture with a cell penetrating peptide.
10. The method of claim 1 , wherein the inhibitor is a peptide of about 11 to about 22 amino acids long, and wherein the peptide comprises residues 386-407 of SEQ ID NO: 1 or a variant thereof.
11. The method of claim 10 , wherein the peptide comprises a variant of residues 386-407 of SEQ ID NO:1, wherein the variant has one or two mutations at positions selected from the group consisting of D389, A392, D393, N395, A396, PAE397-399, E399, E400, N403 ,W404, D406 and E407,and wherein the amino acid positions are based on SEQ ID NO: 1.
12. The method of claim 11 , wherein the variant has a mutation selected from the group consisting of N395K, A396D, PAE(397-399)SQ, E399R, E400R, E400D/N403L, W404D, D406R and E407R.
13. The method of claim 1 , wherein the peptide comprises a variant of SEQ ID NO: 5, and wherein the variant has a mutation selected from the group consisting of D393R, N395K, A396D, PAE(397-399)SQ, E399R, E400R, and E400D/N403L.
14. A method for reducing the progression of tumor growth or decreasing metastasis in a subject having cancer comprising administering an inhibitor of the interaction between metadherin (MTDH) and Staphylococcal nuclease domain-containing 1 (SND1) wherein the inhibitor inhibits SND1 protein interaction with residues 364 to 582 of SEQ ID NO: 1, wherein the inhibitor is a peptide or a fusion protein comprising the peptide linked to one or more polypeptides not generally recognized to be part of the sequence of MTDH, wherein the peptide comprises the amino acid sequence of DWNAPAEEWGN (SEQ ID NO: 5) or a variant thereof, wherein the variant has one or two mutations at positions selected from the group consisting of D393, N395, A396, PAE397-399, E399, E400, and N403, wherein the amino acid positions are based on SEQ ID NO: 1, and wherein the peptide is about 11 to about 22 amino acids long.
15. A method for reducing or decreasing the expansion of tumor initiating cells in a subject comprising administering an inhibitor of the interaction between metadherin (MTDH) and Staphylococcal nuclease domain-containing 1 (SND1) wherein the inhibitor inhibits SND1 protein interaction with residues 364 to 582 of SEQ ID NO: 1, wherein the inhibitor is a peptide or a fusion protein comprising the peptide linked to one or more polypeptides not generally recognized to be part of the sequence of MTDH, wherein the peptide comprises the amino acid sequence of DWNAPAEEWGN (SEQ ID NO: 5) or a variant thereof, wherein the variant has one or two mutations at positions selected from the group consisting of D393, N395, A396, PAE397-399, E399, E400, and N403, wherein the amino acid positions are based on SEQ ID NO: 1, and wherein the peptide is about 11 to about 22 amino acids long.