CAPCNA PEPTIDE THERAPEUTICS FOR CANCER
Administration of compositions comprising cell-permeable caPCNA-derived peptides and their variants reduces the proliferation of cancer cells and also augments cytotoxic effects of chemotherapeutics. The compositions are effective in cells harboring mutations in DNA repair proteins.
1 . A method of inducing cell death in a cancer cell or a pre-malignant cell, the method comprising administering a therapeutically effective amount of a composition comprising a caPCNA peptide molecule, wherein the caPCNA peptide molecule comprises an amino acid sequence selected from LGIPEQEY (SEQ ID NO: 1), LAIPEQEY (SEQ ID NO: 2), LGIAEQEY (SEQ ID NO: 3), LGIPAQEY (SEQ ID NO: 4), LGIPEAEY (SEQ ID NO: 5), LGIPEQAY (SEQ ID NO: 6), LGIAEAEY (SEQ ID NO: 7), LGIPEAAY (SEQ ID NO: 8), LGIAEQAY (SEQ ID NO: 9), and LGIAEAAY (SEQ ID NO: 10), wherein the cell has a mutation in a DNA repair protein.
2 . A method of reducing cellular proliferation of a cancer cell or a pre-malignant cell of an individual, the method comprising administering a therapeutically effective amount of a composition comprising a caPCNA peptide molecule, wherein the caPCNA peptide molecule comprises an amino acid sequence selected from LGIPEQEY (SEQ ID NO: 1), LAIPEQEY (SEQ ID NO: 2), LGIAEQEY (SEQ ID NO: 3), LGIPAQEY (SEQ ID NO: 4), LGIPEAEY (SEQ ID NO: 5), LGIPEQAY (SEQ ID NO: 6), LGIAEAEY (SEQ ID NO: 7), LGIPEAAY (SEQ ID NO: 8), LGIAEQAY (SEQ ID NO: 9), and LGIAEAAY (SEQ ID NO: 10), wherein the individual has one or more mutations in a DNA repair protein.
3 . The method according to claim 1 , wherein the DNA repair protein participates in homologous recombination.
4 . The method according to claim 1 , wherein the protein is selected from BRCA1, BRCA2, PALB2, RAD51, RAD52, XRCC3, MRE11, and/or combinations thereof.
5 . The method according to claim 4 wherein the protein is BRCA1.
6 . The method according to claim 1 , wherein the caPCNA peptide molecule comprises a cell penetrating factor.
7 . The method according to claim 6 wherein the cell penetrating factor is covalently attached or conjugated to the caPCNA peptide molecule.
8 . The method according to claim 6 wherein the cell penetrating factor is recombinantly fused to the caPCNA peptide molecule.
9 . The method according to claim 6 , wherein the cell penetrating factor is a peptide is selected from the amino acid sequences RRRRRRR (SEQ ID NO: 11), RRRRRRRR (SEQ ID NO: 12), RRRRRRRRR (SEQ ID NO: 13), RRRRRRRRRR (SEQ ID NO: 14), RRRRRRRRRRR (SEQ ID NO: 15), RQIKIWFQNRRMKWKK (SEQ ID NO: 16), GRKKRRQRRRPPQ (SEQ ID NO: 17), GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 18), and GRKKRRQRRR (SEQ ID NO: 19).
10 . The method according to claim 9 , wherein the amino acid sequence comprises one or more amino acid D-isomers.
11 . The method according to claim 1 , wherein the composition further comprises a cell surface targeting factor.
12 . The method according to claim 1 , wherein the composition further comprises a nuclear localization sequence.
13 . The method according to claim 1 , wherein the composition is administered intravenously.
14 . The method according to claim 1 , wherein the composition is delivered intratumorally.
15 . The method according to claim 1 , further comprising administering a chemotherapeutic agent.
16 . (canceled)
17 . The method of claim 15 , wherein the chemotherapeutic agent is selected from doxorubicin, irinotecan, cyclophosphamide, chlorambucil, melphalan, methotrexate, cytarabine, fludarabine, 6-mercaptopurine, 5-fluorouracil, capecytabine, cisplatin, carboplatin, oxaliplatin, and any combination thereof.
18 . A method of reducing the effective dose of a chemotherapeutic agent required to treat cancer, the method comprising administering a caPCNA peptide and a chemotherapeutic agent to an individual diagnosed with a cancer associated with one or more mutations in a DNA repair protein.
19 . The method of claim 18 , wherein the effective dose of the chemotherapeutic agent is from about 25% to about 75% less than the standard chemotherapeutic dose for the agent.
20 . The method according to claim 18 wherein the cancer is breast cancer.
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . (canceled)
26 . The method of claim 18 , wherein the chemotherapeutic agent is selected from doxorubicin, irinotecan, cyclophosphamide, chlorambucil, melphalan, methotrexate, cytarabine, fludarabine, 6-mercaptopurine, 5-fluorouracil, capecytabine, cisplatin, carboplatin, oxaliplatin, and any combination thereof.