Combination treatment of cancer with cetuximab and tetrac

• US 9,180,107 B2
• Filed: 03/31/2010
• Issued: 11/10/2015
• Est. Priority Date: 03/31/2009
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Lin, Hung-Yun, Davis, Faith B., Davis, Paul J., Mousa, Shaker A.
• Primary Examiner(s): Shafer, Shulamith H
• Application Number:
  US12/751,375
• Publication Number:
  US 20100255108A1
• Time in Patent Office: 2,050 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Provided herein are compositions and methods for treating cancer by increasing the inhibitory effect of cetuximab on HIF1α expression by administering cetuximab in combination with anti-angiogenic thyroid hormone analogs such as tetrac or triac.

Claims

1. A pharmaceutical composition comprising a combination of cetuximab and an anti-angiogenic thyroid hormone analog selected from the group consisting of tetrac (tetraiodothyroacetic acid), triac (triiodothyroacetic acid) and a combination thereof, wherein the thyroid hormone analog is conjugated via a covalent bond to a polymer, wherein the cetuximab is at least one of encapsulated within said polymer, conjugated via a covalent bond to the polymer and a combination thereof.

2. The pharmaceutical composition of claim 1, wherein the polymer is selected from polyvinyl alcohol, acrylic acid ethylene copolymer, methoxypolyethylene, polyethyleneglycol (PEG), polyacrylic acid, polylactic acid, agarose, polyglycolide, polylactide, PEO, m-PEG, PVA, PLLA, PGA, poly-L-Lysine, Human Serum Albumin, cellulose derivatives, carbomethoxy/ethyl/hydroxypropyl, hyaluronic acid, folate linked cyclodextrin/dextran, sarcosine/amino acid spaced polymer, alginate, carrageenan, pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide (PLG), poly(lactic-co-glycolic) acid (PLGA), polyglycolide, polylysyl glycolide, polylactic acid, or co-polymers thereof, wherein said polymer is formulated into a nanoparticle, wherein said nanoparticle is between 150 and 250 nanometers in size, -and wherein said tetrac binds to the cell surface receptor for thyroid hormone on integrin α

vβ

3.

3. The pharmaceutical composition of claim 2, wherein the thyroid hormone analog is attached to the nanoparticle via a linker.

4. The pharmaceutical composition of claim 3, wherein the linker is between 4 and 15 atoms long.

5. The pharmaceutical composition of claim 1, further comprising an anti-estrogen compound.

6. The pharmaceutical composition of claim 5, wherein the anti-estrogen compound is selected from the group consisting of tamoxifen and aromatase inhibitors.

7. The pharmaceutical composition of claim 2, wherein the nanoparticles further comprise one or more additional chemotherapeutic agents.

8. The pharmaceutical composition of claim 7, wherein the one or more additional chemotherapeutic agents are targeted to the cancer cells.

9. The pharmaceutical composition of claim 1, wherein the combination inhibits PI3K-dependent HIF1α

gene expression.

10. The pharmaceutical composition of claim 9, wherein the combination blocks the inhibitory action of endogenous thyroid hormone on the actions of cetuximab on HIF1α

.

11. A method of treating cancer wherein the cancer is selected from the group consisting of colon cancer, breast cancer, glioblastoma, and adenoid cystic carcinoma, comprising administering a therapeutically effective amount of a combination of the pharmaceutical composition of claim 1 to a patient suffering therefrom.

12. The method of claim 11, wherein the thyroid hormone analog is tetrac.

13. The method of claim 12, wherein tetrac is conjugated via a covalent bond to a polymer selected from polyvinyl alcohol, acrylic acid ethylene co-polymer, methoxypolyethylene, polyethyleneglycol (PEO), polyacrylic acid, poly lactic acid, agarose, polyglycolide, polylactide, PEO, m-PEG, PV A, PLLA, POA, poly-L-lysine, Human Serum Albumin, cellulose derivatives, carbomethoxy/ethyl/hydroxypropyl, hyaluronic acid, folate linked cyclodextrin/dextran, sarcosine/amino acid spaced polymer, alginate, carrageenan, pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide (PLG), poly(lactic-co-glycolic) acid (PLGA), polylysyl glycolide, polylactic acid, polyglycolide, or co-polymers thereof, wherein said polymer is formulated into a nanoparticle, wherein said nanoparticle is between 150 and 250 nanometers in size, and wherein said tetrac binds to the cell surface receptor for thyroid hormone on integrin α

vβ

3.

14. The method of claim 11, further comprising administering an anti-estrogen compound to the subject.

15. The method of claim 14, wherein the anti-estrogen compound is selected from the group consisting of tamoxifen and aromatase inhibitors.

16. The method of claim 13, wherein the nanoparticles further comprise one or more additional chemotherapeutic agents.

17. The method of claim 13, wherein cetuximab is encapsulated within the nanoparticle.

18. The pharmaceutical composition of claim 2, wherein the tetrac is a plasma membrane impermeable form of tetrac, wherein said nanoparticle is a non-reactive nanoparticle which is covalently bound to an outer ring hydroxyl group of the tetrac.

19. The pharmaceutical composition of claim 18 wherein the non-reactive nanoparticle is covalently bonded via a linker.

20. The pharmaceutical composition of claim 18 wherein the linker is between 4-15 atoms long.

21. A pharmaceutical composition comprising a combination of cetuximab and a thyroid hormone analog selected from the group consisting of tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac) and combinations thereof, wherein the cetuximab and the thyroid hormone analog are conjugated to a polymer wherein the polymer is a nanoparticle.