Compositions and methods for inhibiting tumor growth and metastasis

Abstract

Disclosed are compositions and methods useful in the reduction of p11 protein activity in cancer cells. P11 protein is demonstrated to affect plasmin production and activity, MMP activity, plasminogen activation, antiangiogenic plasmin fragment production, cell invasion, tumor development and metastasis. Compositions that modulate levels of p11 either up or down are demonstrated to be effective in reducing tumor development. Also disclosed are cancer treatment methods that employ compositions that modulate p11 activity and clonal cell lines and assays useful for the identification of compositions that modulate p11 activity.

1 - 18 . (canceled)  
     
     
         19 . A method for modulating the activity of p11, the method comprising administering to a cell a composition that modulates the activity of a p11 protein.  
     
     
         20 . The method of  claim 19  wherein the composition comprises a polynucleotide selected from the group consisting of an antisense p11 polynucleotide, a sense p11 polynucleotide, and a small interfering RNA specific to p11.  
     
     
         21 . The method of  claim 19  wherein the cell is a cancer cell.  
     
     
         22 . The method of  claim 20  wherein the cell is selected from the group consisting of a HT1080 fibrosarcoma cell, a LNCaP prostate cancer cell and a CCL-222 colorectal adenocarcinoma cell.  
     
     
         23 . A method of reducing the development of cancer, the method comprising administering to a cancer cell a therapeutically effective amount of a composition that modulates the activity of a p11 protein.  
     
     
         24 . The method of  claim 23  wherein the composition comprises a polynucleotide selected from the group consisting of an antisense p11 polynucleotide, a sense p11 polynucleotide, and a small interfering RNA specific to p11.  
     
     
         25 . (canceled)  
     
     
         26 . The method of  claim 23  wherein the cancer cell is a human cancer cell.  
     
     
         27 . The method of  claim 23  wherein the cancer cell is selected from the group consisting of a HT1080 fibrosarcoma cell, a LNCaP prostate cancer cell and a CCL-222 colorectal adenocarcinoma cell.  
     
     
         28 . A method of inhibiting the growth of a tumor, the method comprising administering to a cancer cell a composition that modulates the activity of a p11 protein.  
     
     
         29 . The method of  claim 28  wherein the composition comprises a polynucleotide selected from the group consisting of an antisense p11 polynucleotide, a sense p11 polynucleotide, and a small interfering RNA specific to p11.  
     
     
         30 . (canceled)  
     
     
         31 . The method of  claim 28  wherein the cancer cell is a human cancer cell.  
     
     
         32 . The method of  claim 28  wherein the cancer cell is selected from the group consisting of a HT 1080 fibrosarcoma cell, a LNCaP prostate cancer cell and a CCL-222 colorectal adenocarcinoma cell.  
     
     
         33 . A method of inhibiting tumor cell invasion, the method comprising administering to the tumor cell a composition, that modulates the activity of a p11 protein.  
     
     
         34 . The method of  claim 33  wherein the composition comprises a polynucleotide selected from the group consisting of an antisense p11 polynucleotide, a sense p11 polynucleotide, and a small interfering RNA specific to p11.  
     
     
         35 . The method of  claim 33  wherein the tumor cell is a human cancer cell.  
     
     
         36 . The method of  claim 33  wherein the tumor cell is selected from the group consisting of a HT1080 fibrosarcoma cell, a LNCaP prostate cancer cell and a CCL-222 colorectal adenocarcinoma cell.  
     
     
         37 - 45 . (canceled)  
     
     
         46 . The method of  claim 20 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:5, SEQ ID NO: 13-SEQ ID NO:16, and SEQ ID NO: 145-SEQ ID NO:160.  
     
     
         47 . The method of  claim 46 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:13-SEQ ID NO:16.  
     
     
         48 . The method of  claim 20 , wherein the sense p11 polynucleotide is comprised of the nucleic acid sequence of SEQ ID NO:17 or a fragment thereof.  
     
     
         49 . The method of  claim 20 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:144.  
     
     
         50 . The method of  claim 49 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:24.  
     
     
         51 . The method of  claim 50 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:22 and SEQ ID NO:24.  
     
     
         52 . The method of  claim 23 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:5, SEQ ID NO: 13-SEQ ID NO:16, and SEQ ID NO: 145-SEQ ID NO:160.  
     
     
         53 . The method of  claim 52 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:13-SEQ ID NO:16.  
     
     
         54 . The method of  claim 23 , wherein the sense p11 polynucleotide is comprised of the nucleic acid sequence of SEQ ID NO:17 or a fragment thereof.  
     
     
         55 . The method of  claim 23 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:144.  
     
     
         56 . The method of  claim 55 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:24.  
     
     
         57 . The method of  claim 56 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:22 and SEQ ID NO:24.  
     
     
         58 . The method of  claim 28 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:5, SEQ ID NO: 13-SEQ ID NO:16, and SEQ ID NO: 145-SEQ ID NO:160.  
     
     
         59 . The method of  claim 58 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:13-SEQ ID NO:16.  
     
     
         60 . The method of  claim 28 , wherein the sense p11 polynucleotide is comprised of the nucleic acid sequence of SEQ ID NO:17 or a fragment thereof.  
     
     
         61 . The method of  claim 28 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:144.  
     
     
         62 . The method of  claim 61 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:24.  
     
     
         63 . The method of  claim 62 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:22 and SEQ ID NO:24.  
     
     
         64 . The method of  claim 33 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:5, SEQ ID NO: 13-SEQ ID NO:16, and SEQ ID NO. 145-SEQ ID NO:160.  
     
     
         65 . The method of  claim 64 , wherein the antisense p11 polynucleotide is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:13-SEQ ID NO:16.  
     
     
         66 . The method of  claim 33 , wherein the sense p11 polynucleotide is comprised of the nucleic acid sequence of SEQ ID NO:17 or a fragment thereof.  
     
     
         67 . The method of  claim 33 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:144.  
     
     
         68 . The method of  claim 67 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:18-SEQ ID NO:24.  
     
     
         69 . The method of  claim 68 , wherein the small interfering RNA is comprised of a sequence selected from the group of nucleic acid sequences consisting of SEQ ID NO:22 and SEQ ID NO:24.