Targeting trastuzumab-resistant HER2+ breast cancer with a HER3-targeting nanoparticle

Patent metadata

Field	Value
Publication number	US-9850293-B2
Application number	US-201514678972-A
Country	US
Kind code	B2
Filing date	Apr 4, 2015
Priority date	Apr 4, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

Disclosed herein are methods of treating cancer in a patient, the method comprising identifying a patient who is resistant to treatment with an anti-HER2 therapy; and administering to the patient a drug delivery molecule, comprising a polypeptide molecule adapted to target and/or penetrate a type of cell; a nucleic acid molecule bound to the polypeptide sequence via electrostatic interactions; and a chemical agent non-covalently linked to the nucleic acid sequence. Also disclosed are methods of inducing apoptosis in an anti-HER2 therapy resistant HER2+ breast cancer cell, the method comprising contacting the anti-HER2 therapy resistant HER2+ breast cancer cell with the drug delivery molecule. Further disclosed herein are methods of treating cancer in a patient, the method comprising identifying a patient who is resistant to anti-HER2 therapy; and administering to the patient a therapeutically effective amount of a drug delivery molecule, comprising a polypeptide molecule adapted to target and/or penetrate a type of cell; and a sulfonated corrole molecule bound to the polypeptide sequence. Finally disclosed herein are methods of inducing apoptosis in an anti-HER2 therapy resistant HER2+ breast cancer cell, the method comprising contacting the anti-HER2 therapy resistant HER2+ breast cancer cell with a drug delivery molecule, comprising a polypeptide molecule adapted to target and/or penetrate a type of cell; and a sulfonated corrole molecule bound to the polypeptide sequence.

First claim

What is claimed is:

1. A method of treating a triple-negative breast cancer in a patient comprising:
administering to the patient a therapeutically effective amount of a drug delivery molecule comprising:
(a) a polypeptide comprising a receptor binding domain of human heregulin-α; an adenovirus penton base protein; and a positively charged domain comprising a plurality of positively-charged amino acid residues that provide a net positive charge to the positively charged domain;
(b) a double-stranded nucleic acid molecule bound to the positively charged domain via electrostatic interactions; and
(c) a chemotherapeutic agent non-covalently linked to the double-stranded nucleic acid molecule;

wherein the triple-negative breast cancer expresses HER3.

2. The method of claim 1 , wherein the positively charged domain comprises a polylysine motif, and wherein the polylysine motif comprises a plurality of contiguous lysines.

3. The method of claim 2 , wherein the polylysine motif is a decalysine.

4. The method of claim 1 , wherein the double-stranded nucleic acid molecule comprises a nucleic acid molecule with the sequence of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.

5. The method of claim 1 , wherein the polypeptide comprises from N-terminus to C-terminus:
a heregulin-a binding domain comprising a sequence according to SEQ ID NO: 13;
a penton base segment comprising a sequence according to SEQ ID NO: 10; and
a decalysine.

6. The method of claim 1 , wherein the chemotherapeutic agent is doxorubicin.

7. The method of claim 1 , wherein the chemotherapeutic agent is intercalated with the double-stranded nucleic acid molecule.

8. The method of claim 1 , wherein the patient is a human.

9. A method of inducing apoptosis in a triple-negative breast cancer cell comprising:
contacting the triple-negative breast cancer cell with a drug delivery molecule comprising:
(a) a polypeptide comprising a receptor binding domain of human heregulin-α; an adenovirus penton base protein; and a positively charged domain comprising a plurality of positively-charged amino acid residues that provide a net positive charge to the positively charged domain;
(b) a double-stranded nucleic acid molecule bound to the positively charged domain via electrostatic interactions; and
(c) a chemotherapeutic agent non-covalently linked to the double-stranded nucleic acid molecule, wherein the chemotherapeutic agent is effective to induce apoptosis of the triple-negative breast cancer cell;

wherein the triple-negative breast cancer cell expresses HER3.

10. The method of claim 9 , wherein the contacting is in vitro.

11. The method of claim 9 , wherein the contacting is in vivo.

12. The method of claim 9 , wherein the breast cancer cell is a human breast cancer cell.

13. The method of claim 9 , wherein the double-stranded nucleic acid molecule comprises a nucleic acid molecule with the sequence of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.

14. A method of killing a triple-negative breast cancer cell comprising:
contacting the triple-negative breast cancer cell with a drug delivery molecule comprising:
(a) a polypeptide comprising a receptor binding domain of human heregulin-a; an adenovirus penton base protein; and a positively charged domain comprising a plurality of positively-charged amino acid residues that provide a net positive charge to the positively charged domain;
(b) a double-stranded nucleic acid molecule bound to the positively charged domain via electrostatic interactions; and
(c) a chemotherapeutic agent non-covalently linked to the double-stranded nucleic acid molecule;

wherein the triple-negative breast cancer cell expresses HER3.

Assignees

• Cedars Sinai Medical Center

Inventors

• Medina-Kauwe Lali K
• Sims Jessica
• Taguaim Michael
• Hanson Chris
• Cui Xiaojiang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• C07K14/4756 Primary

  Neuregulins, i.e. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title