Combination Treatment of Cancer With Cetuximab and Tetrac

• US 20100255108A1
• Filed: 03/31/2010
• Published: 10/07/2010
• Est. Priority Date: 03/31/2009
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Davis, Paul J., Davis, Faith B., Lin, Hung-Yun
• Granted Patent: US 9,180,107 B2
• Time in Patent Office: Days
• US Class Current: 424/491
• 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 for treating cancer comprising a combination of cetuximab and an anti-angiogenic thyroid hormone analog, wherein the combination inhibits expression of hypoxia-inducible factor 1-α

(HIF1α

) in cancer cells.

2. The pharmaceutical composition of claim 1, wherein the cancer cells are selected from the group consisting of:

breast cancer, lung cancer, kidney cancer, thyroid cancer, brain cancer (glioma), ovarian cancer, pancreatic cancer, prostate cancer, plasma cell cancer (myeloma), squamous cell head-and-neck cancer, liver cancer, muscle cancer (sarcoma), colon cancer, neuroblastoma, lymphoma, adenoid carcinoma, stomach cancer, skin cancer, melanoma, basal cell carcinoma, and squamous cell carcinoma.

3. The pharmaceutical composition of claim 1, wherein the thyroid hormone analog is tetrac or triac (triiodothyroacetic acid).

4. The pharmaceutical composition of claim 3, wherein the thyroid hormone analog is tetrac.

5. The pharmaceutical composition of claim 3, wherein the thyroid hormone analog is triac.

6. The pharmaceutical composition of claim 4, wherein the tetrac is conjugated via a covalent bond to a polymer selected from polyvinyl alcohol, acrylic acid ethylene co-polymer, 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.

7. The pharmaceutical composition of claim 6, wherein the tetrac is attached to the nanoparticle via a linker.

8. The pharmaceutical composition of claim 7, wherein the linker is between 4 and 15 atoms long.

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

10. The pharmaceutical composition of claim 9, wherein the anti-estrogen compound is selected from the group consisting of tamoxifen and aromatase inhibitors.

11. The pharmaceutical composition of claim 6, wherein the nanoparticles further comprise one or more additional chemotherapeutic agents.

12. The pharmaceutical composition of claim 11, wherein the one or more additional chemotherapeutic agents are targeted to the cancer cells.

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

gene expression.

14. The pharmaceutical composition of claim 13, wherein the combination blocks the inhibitory action of endogenous thyroid hormone on the actions of cetuximab on HIF1α

.

23. The pharmaceutical composition of claim 6, wherein cetuximab is encapsulated within the nanoparticle.

15. A method of treating cancer comprising administering a therapeutically effective amount of a combination of cetuximab and an anti-angiogenic thyroid hormone analog to a patient suffering therefrom.

16. The method of claim 15, wherein the thyroid hormone analog is tetrac or triac.

17. The method of claim 16, wherein the thyroid hormone analog is tetrac.

18. The method of claim 17, wherein tetrac is conjugated via a covalent bond to a polymer selected from polyvinyl alcohol, acrylic acid ethylene co-polymer, 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), 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.

19. The method of claim 15, further comprising administering an anti-estrogen compound to the subject.

20. The method of claim 19, wherein the anti-estrogen compound is selected from the group consisting of tamoxifen and aromatase inhibitors.

21. The method of claim 18, wherein the nanoparticles further comprise one or more additional chemotherapeutic agents.

22. The method of claim 18, wherein cetuximab is encapsulated within the nanoparticle.