Fas/FasL or other death receptor targeted methods and compositions for killing tumor cells

1. A method for inhibiting proliferation of brain tumor cells, which comprises:

administering to brain tumor cells a siNA agent that reduces the amount of RNA encoding a Fas/FasL apoptosis gating polypeptide in an amount sufficient to inhibit proliferation of the brain tumor cells,

wherein the Fas/FasL apoptosis gating polypeptide is a FAPP2 polypeptide or a PATZ1 polypeptide, and

wherein the siNA agent comprises one or more of the nucleotide sequences:

(SEQ ID NO: 26)

5′-GAUGGAUCUUGUUGGAAAUUU-3′

(SEQ ID NO: 27)

5′-AUUUCCAACAAGAUCCAUCUU-3′

(SEQ ID NO: 28)

5′-GAUGGAUCUUGUUGGAAAUUsU-3′

(SEQ ID NO: 29)

5′-AUUUCCAACAAGAUCCAUCUsU-3′

(SEQ ID NO: 30)

5′-GAuGGAucuuGuuGGAAAuusu-3′

(SEQ ID NO: 31)

5′-AUUUCcAACAAGAUCcAUCUsU-3′

(SEQ ID NO: 32)

5′-GUCUAUGGAAGAAAUAGUUUU-3′

(SEQ ID NO: 33)

5′-UUACUACUACUACUACUACUU-3′

(SEQ ID NO: 34)

5′-GUCUAUGGAAGAAAUAGUUUsU-3′

(SEQ ID NO: 35)

5′-UUACUACUACUACUACUACUsU-3′

(SEQ ID NO: 36)

5′-GucuAuGGAAGAAAuAGuuusU-3′

(SEQ ID NO: 37)

5′-UuACuACuACuACuACuACUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.

2. The method of claim 1 , wherein the brain tumor cells comprise glioma cells.

3. The method of claim 1 , wherein the brain tumor cells are glioma cells.

4. The method of claim 2 , wherein the brain tumor cells are human cells.

5. The method of claim 3 , wherein the brain tumor cells are human cells.

6. The method of claim 4 , wherein the reduction of FAPP2 polypeptide or PATZ1 polypeptide sensitizes the cells to Fas or FasL mediated apoptosis.

7. The method of claim 5 , wherein the reduction of FAPP2 polypeptide or PATZ1 polypeptide sensitizes the cells to Fas or FasL mediated apoptosis.

8. The method of claim 6 , wherein a FAPP2 targeted ribozyme comprises the nucleotide sequence:

(SEQ ID NO: 1)

5′-NNNNNNNCUGAUGAGpdpdpdpdCGAANNNNNNNNN-3′.

wherein N indicates any of DNA bases A, C, G, T, or any of RNA bases A, C, G, U, or any of 2′-O-methylated RNA bases A, C, G, U,

wherein A, C, G, indicate DNA bases A, C, G, or RNA bases A, C, G, or 2′-O-methyl RNA bases A, C, G,

wherein U indicates a RNA base U or 2′-O-methyl RNA base U, and

wherein pd indicates propanediol linkage.

9. The method of claim 6 , wherein the siNA is siRNA.

10. The method of claim 9 , wherein the siRNA comprises a phosphorothioate linkage.

11. The method of claim 10 , wherein the siRNA comprises a 2′-O-methyl modification.

12. The method of claim 9 , wherein the FAPP2 targeted siRNA comprises one or both of the nucleotide sequences:

(SEQ ID NO: 26)

5′-GAUGGAUCUUGUUGGAAAUUU-3′

(SEQ ID NO: 27)

5′-AUUUCCAACAAGAUCCAUCUU-3′.

13. The method of claim 10 , wherein the FAPP2 targeted siRNA comprises one or both of the nucleotide sequences:

(SEQ ID NO: 28)

5′-GAUGGAUCUUGUUGGAAAUUsU-3′

(SEQ ID NO: 29)

5′-AUUUCCAACAAGAUCCAUCUsU-3′

wherein s is a phosphorothioate linkage.

14. The method of claim 11 , wherein the FAPP2 targeted siRNA comprises one or both of the nucleotide sequences:

(SEQ ID NO: 30)

5′-GAuGGAucuuGuuGGAAAuusu-3′

(SEQ ID NO: 31)

5′-AUUUCcAACAAGAUCcAUCUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.

15. The method of claim 9 wherein the PATZ1 targeted siRNA comprises one or more of the nucleotide sequences:

(SEQ ID NO: 32)

5′-GUCUAUGGAAGAAAUAGUUUU-3′

(SEQ ID NO: 33)

5′-UUACUACUACUACUACUACUU-3′.

16. The method of claim 10 , wherein the PATZ1 targeted siRNAi comprises one or more of the nucleotide sequences:

(SEQ ID NO: 34)

5′-GUCUAUGGAAGAAAUAGUUUsU-3′

(SEQ ID NO: 35)

5′-UUACUACUACUACUACUACUsU-3′

wherein s is a phosphorothioate linkage.

17. The method of claim 11 , wherein the PATZ1 targeted siRNA comprises one or more of the nucleotide sequences:

(SEQ ID NO: 36)

5′-GucuAuGGAAGAAAuAGuuusU-3′

(SEQ ID NO: 37)

5′-UuACuACuACuACuACuACUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.

18. A method for treating a brain tumor in a subject, which comprises:

administering to a subject in need thereof a siNA agent that reduces the amount of RNA encoding a FAPP2 polypeptide or a PATZ1 polypeptide in an amount sufficient to inhibit proliferation of cells in the brain tumor in the subject,

wherein the siNA agent comprises comprises one or more of the nucleotide sequences:

(SEQ ID NO: 26)

5′-GAUGGAUCUUGUUGGAAAUUU-3′

(SEQ ID NO: 27)

5′-AUUUCCAACAAGAUCCAUCUU-3′

(SEQ ID NO: 28)

5′-GAUGGAUCUUGUUGGAAAUUsU-3′

(SEQ ID NO: 29)

5′-AUUUCCAACAAGAUCCAUCUsU-3′

(SEQ ID NO: 30)

5′-GAuGGAucuuGuuGGAAAuusu-3′

(SEQ ID NO: 31)

5′-AUUUCcAACAAGAUCcAUCUsU-3′

(SEQ ID NO: 32)

5′-GUCUAUGGAAGAAAUAGUUUU-3′

(SEQ ID NO: 33)

5′-UUACUACUACUACUACUACUU-3′

(SEQ ID NO: 34)

5′-GUCUAUGGAAGAAAUAGUUUsU-3′

(SEQ ID NO: 35)

5′-UUACUACUACUACUACUACUsU-3′

(SEQ ID NO: 36)

5′-GucuAuGGAAGAAAuAGuuusU-3′

(SEQ ID NO: 37)

5′-UuACuACuACuACuACuACUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.

19. A method for treating a brain tumor in a subject, which comprises administering to a subject in need thereof a ribozyme that reduces the amount of RNA encoding a FAPP2 polypeptide or a PATZ1 polypeptide in an amount sufficient to inhibit proliferation of cells in the brain tumor in the subject,

wherein the ribozyme comprises one or more of the nucleotide sequences:

(SEQ ID NO: 26)

5′-GAUGGAUCUUGUUGGAAAUUU-3′

(SEQ ID NO: 27)

5′-AUUUCCAACAAGAUCCAUCUU-3′

(SEQ ID NO: 28)

5′-GAUGGAUCUUGUUGGAAAUUsU-3′

(SEQ ID NO: 29)

5′-AUUUCCAACAAGAUCCAUCUsU-3′

(SEQ ID NO: 30)

5′-GAuGGAucuuGuuGGAAAuusu-3′

(SEQ ID NO: 31)

5′-AUUUCcAACAAGAUCcAUCUsU-3′

(SEQ ID NO: 32)

5′-GUCUAUGGAAGAAAUAGUUUU-3′

(SEQ ID NO: 33)

5′-UUACUACUACUACUACUACUU-3′

(SEQ ID NO: 34)

5′-GUCUAUGGAAGAAAUAGUUUsU-3′

(SEQ ID NO: 35)

5′-UUACUACUACUACUACUACUsU-3′

(SEQ ID NO: 36)

5′-GucuAuGGAAGAAAuAGuuusU-3′

(SEQ ID NO: 37)

5′-UuACuACuACuACuACuACUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.

20. A composition comprising the nucleic acid:

(SEQ ID NO: 1)

5′-NNNNNNNCUGAUGAGpdpdpdpdCGAANNNNNNNNN-3′

wherein N indicates any of DNA bases A, C, G, T, or any of RNA bases A, C, G, U, or any of 2′-O-methylated RNA bases A, C, G, U,

wherein A, C, G, indicate DNA bases A, C, G, or RNA bases A, C, G, or 2′ 0-methyl RNA bases A, C, G,

wherein U indicates a RNA base U or 2′-O-methyl RNA base U, and

wherein pd indicates propanediol linkage.

21. A composition comprising one or both of the following nucleic acids:

(SEQ ID NO: 30)

5′-GAuGGAucuuGuuGGAAAuusu-3′

(SEQ ID NO: 31)

5′-AUUUCcAACAAGAUCcAUCUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.

22. A composition comprising one or both of the following nucleic acids:

(SEQ ID NO: 36)

5′-GucuAuGGAAGAAAuAGuuusU-3′

(SEQ ID NO: 37)

5′-UuACuACuACuACuACuACUsU-3′

wherein s is a phosphorothioate linkage and lowercase nucleotide designations designate a nucleotide having a 2′-O-methyl modification.