Polypeptides for treatment of cancer
The present-disclosure provides methods of treating cancer with certain co-activator of activator protein-1 and estrogen receptor (CAPER)-based polypeptides. In certain embodiments, the methods of the-disclosure target only cancerous cells without adversely affecting non-cancerous cells.
1. A method of treating or ameliorating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a polypeptide consisting essentially of:
(a) amino acid residues 356-400 of co-activator of activator protein-1 and estrogen receptor (CAPER) isoform HCC1.3 (SEQ ID NO. 1);
or
(b) amino acid residues 356-400 of CAPER isoform HCC1.4 (SEQ ID NO. 2).
2. The method of claim 1 , wherein the cancer comprises at least one of breast cancer, brain cancer, and lung cancer.
3. The method of claim 2 , wherein the breast cancer comprises triple negative breast cancer (TNBC) or estrogen-positive breast cancer.
4. The method of claim 1 , wherein the polypeptide is derivatized at at least one amino acid residue, wherein the derivatization comprises methylation, amidation, or acetylation.
5. The method of claim 1 , wherein the polypeptide is fused to a cell penetrating peptide, optionally wherein the cell penetrating peptide is any of SEQ ID NOs. 10-47.
6. The method of claim 5 , wherein the polypeptide is fused to the cell penetrating peptide via a linker, optionally wherein the linker comprises a polyethylene glycol PEG) chain, a peptide, or a peptide nucleic acid (PNA), wherein the optional linker peptide optionally comprises less than about 50 amino acids.
7. The method of claim 1 , wherein the polypeptide binds to at least one of the following:
(a) the c-Jun component of activator protein-1 (AP-1) with an equilibrium dissociation constant (K D ) ranging from about 5_nM to about 50_nM, optionally wherein binding of the polypeptide to the c-Jun component of the activator protein-1 (AP-1) inhibits, at least partially, binding of the full-length CAPER protein to the c-Jun component of AP-1; and
(b) the estrogen receptor (ER)α with an equilibrium dissociation constant (K D ) ranging from about 5 nM to about 50 nM, optionally wherein binding of the polypeptide to the ERα inhibits, at least partially, binding of the full-length CAPER protein to the ERα.
8. The method of claim 1 , wherein the administering induces DNA damage or apoptosis in cancer cells, optionally wherein the administering does not cause any damage, or causes insignificant, apoptosis, or DNA damage in non-cancerous cells.
9. The method of claim 1 , wherein the polypeptide is administered as part of a pharmaceutical composition.
10. The method of claim 1 , wherein the subject is not administered any additional chemotherapeutic agent or anti-cell proliferation agent.
11. The method of claim 1 , further comprising administering to the subject at least one additional agent selected from radiation, a chemotherapeutic agent, an anti-cell proliferation agent, a gene therapy agent, and an immunotherapy agent.
12. The method of claim 11 , wherein the polypeptide and the at least one additional agent are co-administered to the subject, optionally wherein the polypeptide and the at least one additional agent are coformulated.
13. The method of claim 11 , wherein the at least one additional agent is selected from taxotere, cyclophosphamide, paclitaxel, fluorouracil, doxorubicin, cycloheximide, olaparib and temozolomide.
14. The method of claim 1 , wherein the subject is a mammal, which is optionally human.