Polypeptide inhibitor of de novo lipogenesis in cancer cells

Abstract

Disclosed herein is a method for treating cancer in a subject that involves administering to the subject a therapeutically effective amount of a composition comprising a polypeptide that comprises an amino acid sequence corresponding to at the C-terminal SUMO-interacting motif (SIM2) of a DAXX protein. The disclosed polypeptide is not a functional DAXX protein but competes with endogenous DAXX for binding to SUMO.

1 . A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising a polypeptide, wherein the polypeptide comprises an amino acid sequence corresponding to at least the C-terminal SUMO-interacting motif (SIM2) of a DAXX protein, and wherein the polypeptide lacks amino acids 1 to 728 of the DAXX protein. 
     
     
         2 . The method of  claim 1 , wherein the polypeptide comprises at least amino acids 729 to 740 of human DAXX protein, and wherein the polypeptide lacks at least amino acids 1 to 728 of human DAXX protein. 
     
     
         3 . The method of  claim 1 , wherein the polypeptide comprises of the amino acid sequence DPEEIIVLSDSD (SEQ ID NO:1, SIM2), or a variant thereof having one or two conservative amino acid substitutions that binds SUMO-1. 
     
     
         4 . The method of  claim 1 , wherein the polypeptide consists of the amino acid sequence DPEEIIVLSDSD (SEQ ID NO:1, SIM2), or a variant thereof having one or two conservative amino acid substitutions that binds SUMO-1. 
     
     
         5 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence selected from the group comprising DPDDIIVLSDSD (SEQ ID NO:2, SIM008), DPEEIIVLSESE (SEQ ID NO:3, SIM009), DPEEIIVLDDDD (SEQ ID NO:4, SIM010), DPEEKIVLSDSD (SEQ ID NO:5, SIM011), DPEEIIDLSDSD (SEQ ID NO:6, SIM012), EPEEIIVLSDSD (SEQ ID NO:7, SIM013), and IIVLSDS (SEQ ID NO:8, SIM014). 
     
     
         6 . The method of  claim 1 , wherein the polypeptide comprises the amino acid sequence X 1 PX 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11  (SEQ ID NO:9), wherein X 1  is D or E, X 2  is E or D, X 3  is E or D, X 4  is I, V or L, X 5  is I, V, or L, X 6  is V, I, or L, X 7  is L, I, or V, X 8  is S, T, E or D, X 9  is D or E, X 10  is S, T, E or D, AND X 11  is D or E. 
     
     
         7 . The method  claim 1 , wherein the cancer is breast cancer, prostate cancer, or colon cancer. 
     
     
         8 . The method of  claim 1 , further comprising administering to the subject a checkpoint inhibitor. 
     
     
         9 . A composition comprising a polypeptide in a pharmaceutically acceptable excipient, wherein the polypeptide comprises an amino acid sequence corresponding to at least the C-terminal SUMO-interacting motif (SIM2) of a DAXX protein, wherein the polypeptide lacks amino acids 1 to 728 of the DAXX protein, and wherein the excipient comprises amino acids 729 to 740. 
     
     
         10 . The composition of  claim 9 , wherein the polypeptide is encapsulated in a biocompatible nanoparticle. 
     
     
         11 . The composition of  claim 9 , wherein the polypeptide are specifically formulated in a vehicle consisting of 2-Hydroxypropyl)-β-cyclodextrin (HPBCD) solution in a mixture with polyethylene glycols (PEG) for cancer therapy.