Phenotypic reversion of pancreatic carcinoma cells

Abstract

The present invention provides peptides (including analogs and derivatives thereof) corresponding to residues 96-110 and 35-47 of ras-p2 1, which peptides have attached thereto a membrane-penetrating leader sequence. The subject peptides, analogs and derivatives thereof are useful in treatment of cancers and have been shown to induce phenotypic reversion of pancreatic cancer cells to non-cancerous cells. Pharmaceutical compositions comprising one or more subject peptides are also provided by the present invention. The present invention further provides replication incompetent Adenovirus (AdV) vectors comprising a promoter sequence and a nucleotide sequence encoding a subject peptide. Methods of treating cancer by administering one or more subject peptides, pharmaceutical compositions, and/or AdV vectors are also provided.

1 . A peptide comprising at least about ten contiguous amino acids of the amino acid sequence: YREQIKRVKDSDDVP (SEQ ID NO:1), or an analog or derivative thereof, wherein said peptide, analog, or derivative thereof comprises a membrane-penetrating leader sequence attached thereto. 
     
     
         2 . A peptide comprising at least about ten contiguous amino acids of the amino acid sequence: TIEDSYRKQVVID (SEQ ID NO:2) or an analog or derivative thereof wherein said peptide, analog, or derivative thereof comprises a membrane-penetrating leader sequence attached thereto. 
     
     
         3 . The peptide, analog or derivative thereof of  claim 1  or  2  wherein the membrane-penetrating leader sequence is located at the carboxy terminal end of the peptide, analog, or derivative thereof. 
     
     
         4 . The peptide, analog or derivative thereof according to  claim 1  or  2  wherein the leader sequence comprises predominantly positively charged amino acid residues. 
     
     
         5 . The peptide, analog or derivative thereof according to  claim 1  or  2  wherein the leader sequence is at least one of penetratin, Arg  8 , TAT of HIV1, D-TAT, R-TAT, SV40-NLS, nucleoplasmin-NLS, HIV REV, FHV coat, BMV GAG, HTLV-II (REX), CCMV GAG, P22N, Lambda N, Delta N, yeast PRP6, human U2AF, human C-FOS, human C-JUN, yeast GCN4, or p-vec. 
     
     
         6 . The peptide, analogue, or derivative thereof of  claim 5  wherein the penetratin leader sequence has the amino acid sequence: KKWKMRRNQFWVKVQRG (SEQ ID NO:3). 
     
     
         7 . A pharmaceutical composition comprising at least one of the peptides or analogs or derivatives thereof comprising a membrane-penetrating leader sequence according to  claim 1  or  2  admixed with a pharmaceutically acceptable carrier. 
     
     
         8 . A pharmaceutical composition comprising at least one of the peptides, analogs, or derivatives thereof comprising a membrane-penetrating leader sequence according to  claim 3  admixed with a pharmaceutically acceptable carrier. 
     
     
         9 . A pharmaceutical composition comprising at least one of the peptides, analogs, or derivatives thereof comprising a membrane-penetrating leader sequence according to  claim 5  admixed with a pharmaceutically acceptable carrier 
     
     
         10 . A method of treating a patient suffering from cancer, said method comprising administering to said patient a therapeutically effective amount of at least one peptide, analog or derivative thereof comprising a membrane penetrating leader sequence according to  claim 1  or  2 . 
     
     
         11 . A method of treating a patient suffering from cancer, said method comprising administering to said patient a therapeutically effective amount of at least one peptide, analog, or derivative thereof comprising a membrane penetrating leader sequence according to  claim 3 . 
     
     
         12 . A method of treating a patient suffering from cancer, said method comprising administering to said patient a therapeutically effective amount of at least one peptide, analog, or derivative thereof comprising a membrane penetrating leader sequence according to  claim 4 . 
     
     
         13 . A method of treating a patient suffering from cancer, said method comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 7 . 
     
     
         14 . A method of treating a patient suffering from cancer, said method comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 8 . 
     
     
         15 . The method of  claim 10  wherein the treatment results in phenotypic reversion of cancerous cells into non-cancerous cells. 
     
     
         16 . The method of  claim 11  wherein the treatment results in phenotypic reversion of cancerous cells into non-cancerous cells. 
     
     
         17 . The method of  claim 12  wherein the treatment results in phenotypic reversion of cancerous cells into non-cancerous cells. 
     
     
         18 . The method of  claim 13  wherein the treatment results in phenotypic reversion of cancerous cells into non-cancerous cells. 
     
     
         19 . The method of  claim 14  wherein the treatment results in phenotypic reversion of cancerous cells into non-cancerous cells. 
     
     
         20 . A replication incompetent Adenovirus (AdV) vector comprising a promoter sequence operably linked to a nucleotide sequence encoding a peptide, wherein the peptide comprises at least about ten contiguous amino acids of the amino acid sequence: YREQIKRVKDSDDVP (SEQ ID NO: 1), or an analog or derivative thereof. 
     
     
         21 . A replication incompetent Adenovirus (AdV) vector comprising a promoter sequence operably linked to a nucleotide sequence encoding a peptide, wherein the peptide comprises at least about ten contiguous amino acids of the amino acid sequence: TIEDSYRKQVVID (SEQ ID NO: 2), or an analog or derivative thereof. 
     
     
         22 . A method of treating a patient suffering from cancer, said method comprising administering to the patient, a therapeutically effective amount of the AdV vector of  claim 20  or  21 . 
     
     
         23 . A method of inducing phenotypic reversion of cancerous cells to non-cancerous cells in a subject, said method comprising administering to the subject, a therapeutically effective amount of the AdV vector of  claim 20  or  21 . 
     
     
         24 . The method of  claim 23  wherein the cancerous cells are colon cancer cells, pancreatic cancer cells, non-small cell carcinoma of the lung, gastric cancer cells, bladder cancer cells or mesothelioma cells. 
     
     
         25 . The method of  claim 10  wherein the cancer is a ras-induced cancer. 
     
     
         26 . The method of  claim 25  wherein the ras-induced cancer is colon cancer, pancreatic cancer, non-small cell carcinoma of the lung, gastric cancer, bladder cancer or mesothelioma.