Antagonists of muc1

Abstract

The present invention is directed to improved compositions for cellular delivery of peptides. Using segments of only 3-5 positively-charged residues, one can effectively transfer peptides, including therapeutic peptides, into cells. Also provided are modified peptides such as those include stapled and cyclized peptide technology, as well as peptoids/peptidomimetics.

1 - 25 . (canceled) 
     
     
         26 . A method of inhibiting MUC1-positive cancer in a subject comprising administering to the subject a MUC1 peptide of 50 residues or less and comprising at least 5 consecutive MUC1 residues and no more than 20 consecutive MUC1 residues and comprising the sequence CQC (SEQ ID NO:4), wherein:
 (i) the amino-terminal cysteine of CQC is covered on its NH 2 -terminus by at least one amino acid residue that need not correspond to the native MUC1 transmembrane sequence; and   (ii) the peptide comprises 3-5 consecutive positively-charged amino acid residues in addition to those positively-charged amino acid residues corresponding to native MUC1 residues.   
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 27 , wherein the sequence comprises CQCRR, CQCRRR, CQCRRRR, CQCRRK, or CQCRRKN. 
     
     
         29 . The method of  claim 26 , wherein the peptide contains no more than 10 consecutive residues, 11 consecutive residues, 12 consecutive residues, 13 consecutive residues, 14 consecutive residues, 15 consecutive residues, 16 consecutive residues, 17 consecutive residues, 18 consecutive residues or 19 consecutive residues of MUC1. 
     
     
         30 . The method of  claim 26 , wherein the cancer is a solid tumor. 
     
     
         31 . The method of  claim 26 , wherein the cancer is lung cancer, brain cancer, head & neck cancer, breast cancer, skin cancer, liver cancer, pancreatic cancer, stomach cancer, colon cancer, rectal cancer, uterine cancer, cervical cancer, ovarian cancer, testicular cancer, skin cancer or esophageal cancer. 
     
     
         32 . The method of  claim 26 , where the MUC1-positive cell is a leukemia or myeloma cell. 
     
     
         33 . The method of  claim 32 , wherein the cell is a acute myeloid leukemia, chronic myelogenous leukemia or multiple myeloma. 
     
     
         34 . The method of  claim 26 , wherein the 3-5 positively-charged amino acid residues are located at the C-terminus of the peptide, are located at the N-terminus of the peptide, or are split between the N- and C-termini of the peptide. 
     
     
         35 . The method of  claim 26 , wherein the peptide comprises 1, 2, 3 or 4 positively-charged amino acids corresponding to native MUC1 residues. 
     
     
         36 . The method of  claim 26 , wherein (a) the 3-5 positively-charged amino acid residues are arginine and/or lysine, and/or (b) the positively-charged amino acid residues corresponding to native MUC1 residues are arginine and/or lysine. 
     
     
         37 . The method of  claim 26 , wherein administering comprises intravenous, intra-arterial, oral, intratumoral, subcutaneous, topical or intraperitoneal administration. 
     
     
         38 . The method of  claim 26 , wherein administering comprises local, regional, systemic, or continual administration. 
     
     
         39 . The method of  claim 26 , further comprising administering to the subject a second cancer-cancer therapy. 
     
     
         40 . The method of  claim 39 , wherein the second anti-cancer therapy is administered prior to the peptide. 
     
     
         41 . The method of  claim 39 , wherein the second anti-cancer therapy is administered after the peptide. 
     
     
         42 . The method of  claim 39 , wherein the second anti-cancer therapy is administered at the same time as the peptide. 
     
     
         43 . The method of  claim 26 , wherein the subject is a human. 
     
     
         44 . The method of  claim 26 , wherein the peptide is administered at 0.1-500 mg/kg/d. 
     
     
         45 . The method of  claim 26 , wherein the peptide is administered at 10-100 mg/kg/d. 
     
     
         46 . The method of  claim 26 , wherein the peptide is administered daily. 
     
     
         47 . The method of  claim 46 , wherein the peptide is administered daily for 7 days, 2 weeks, 3 weeks, 4 weeks, one month, 6 weeks, 8 weeks, two months, 12 weeks, or 3 months. 
     
     
         48 . The method of  claim 26 , wherein the peptide is administered weekly. 
     
     
         49 . The method of  claim 48 , wherein the peptide is administered weekly for 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks. 
     
     
         50 . The method of  claim 26 , wherein the peptide comprises all L amino acids. 
     
     
         51 . The method of  claim 26 , wherein the peptide comprises all D amino acids. 
     
     
         52 . The method of  claim 26 , wherein the peptide comprises a mix of L and D amino acids. 
     
     
         53 . The method of  claim 26 , wherein the peptide is a stapled peptide. 
     
     
         54 . The method of  claim 26 , wherein the peptide is a cyclized peptide. 
     
     
         55 . The method of  claim 26 , wherein the peptide is a peptidomimetic or peptoid. 
     
     
         56 . The method of  claim 26 , wherein inhibiting comprises inhibiting growth of a cancer cell. 
     
     
         57 . The method of  claim 26 , wherein inhibiting comprises inhibiting proliferation of a cancer cell. 
     
     
         58 . The method of  claim 26 , wherein inhibiting comprises inhibiting cancer cell metastasis. 
     
     
         59 . The method of  claim 26 , wherein inhibiting comprises reducing tumor burden. 
     
     
         60 . The method of  claim 26 , wherein the peptide is encapsulated or embedded in a delivery vehicle. 
     
     
         61 - 75 . (canceled) 
     
     
         76 . The method of  claim 26 , wherein the 3-5 positively-charged residues are located at the NH 2 -terminus of the peptide.