METHODS FOR SCREENING PATIENTS FOR RESISTANCE TO ANGIOINHIBITION, TREATMENT AND PROPHYLAXIS THEREOF

• US 20150139934A1
• Filed: 11/18/2014
• Published: 05/21/2015
• Est. Priority Date: 11/18/2013
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: MOUSA, SHAKER A., DAVIS, PAUL J.
• Granted Patent: US 10,060,934 B2
• Time in Patent Office: Days
• US Class Current: 424/78.31
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/7014 (Neo)vascularisation - Angiogenesis
• CPC Class Codes: G01N 33/5088 of vertebrates
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G01N 33/743 Steroid hormones
• CPC Class Codes: G01N 33/78 Thyroid gland hormones , e.g. T3, T4, TBH, TBG or their receptors

Abstract

A method for screening a patient for angioinhibition resistance and treating said patient having a disease susceptible to treatment via an anti-angiogenic agent. The screening method includes an assay for identifying the presence of angioinhibition resistance in patients by collecting patient blood or serum and subjecting it to a Chick Chorioallantoic Membrane (CAM) angiogenesis assay configured for accepting a human tumor wherein the human tumor xenograft includes a vasculature system. The screening method and assay further includes steps that include using the CAM results for identifying the endogenous pro-angiogenic non-peptide hormone concentrations of the blood sample by calculating the vascular activity of the vasculature system of the human tumor xenograft in the presence of anti-angiogenic drugs and inducing in the patient, a state of subclinical hypothyroidism prior to commencing anti-angiogenic treatment.

Claims

1. A method for screening a patient for angioinhibition resistance and treating said patient having a disease susceptible to treatment via an anti-angiogenic agent, comprising the steps of:

collecting a blood or serum sample from the patient;

performing a Chick Chorioallantoic Membrane (CAM) angiogenesis assay configured for using the collected blood or serum sample from the patient, wherein the CAM includes a human tumor xenograft having a vasculature system;

identifying a concentration of an endogenous pro-angiogenic non-peptide hormone of the blood sample by statistically analyzing a number of vessel branches formed in the presence of the anti-angiogenic agent during the CAM; and

inducing in the patient, a state of subclinical hypothyroidism.

2. The method of claim 1, wherein the disease susceptible to treatment via an anti-angiogenic agent is selected from the group consisting of primary or metastatic tumors, adenoid carcinoma, breast cancer, kidney cancer, colon cancer, glioblastoma multiforme, head-and-neck cancer, hepatoma, lung cancer, lymphoma, melanoma, basal cell carcinoma, squamous cell carcinoma, myeloma, neuroblastaoma, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, carcinoma, stomach cancer, thyroid cancer, diabetic retinopathy, wet macular degeneration, arthritis, Parkinson'"'"'s Disease, Alzheimer'"'"'s Disease or a combination of diseases thereof.

3. The method of claim 1, wherein the endogenous pro-angiogenic non-peptide hormone content is a concentration of free T₄ or T₃ in the blood or serum sample.

4. The method of claim 1 further comprising the step of quantifying vascular branch points in the CAM angiogenesis assay, statistically comparing activities selected from one or more biological fluids, one or more pharmacological agents or endogenous growth factors.

5. The method of claim 1, wherein the anti-angiogenic agent is an anti-angiogenic thyroid hormone analog.

6. The method of claim 5, wherein the anti-angiogenic thyroid hormone analog is tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac), or a combination thereof.

7. The method of claim 6, wherein the anti-angiogenic thyroid hormone analog is further conjugated to a polymer, wherein the polymer is a nanoparticle.

8. The method of claim 7, wherein the polymer is selected from the group consisting of polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethylene glycol (PEG), methoxypolyethylene glycol-poly(lactide-co-glycolide), polyacrylic acid, polylactic acid, agarose, polyglycolide, polyethylene oxide, m-PEG, polyvinyl alcohol, polyglycolic acid, poly-L-lysine, Human Serum Albumin, carboxymethylcellulose derivatives, carboethylcellulose derivatives, carboxyhydroxypropylcellulose derivatives, hyaluronic acid, folate linked cyclodextrin, folate linked dextran, alginate, carrageenan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide, poly(lactic-co-glycolic) acid (PLGA), polylysyl glycolide, polyglycolide, polylactide, or co-polymers thereof.

9. The method of claim 1, further comprising the step of administering a compound to the patient after inducing the state of subclinical hypothyroidism, wherein the compound is an anti-angiogenic agent, an anti-angiogenic agent encapsulating a chemotherapeutic agent, an anti-angiogenic agent encapsulating an anti-inflammatory agent, or a combination of compounds thereof.

10. The method of claim 4, wherein the endogenous growth factors are basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet derived endothelial growth factor (PDGF).

11. The method of claim 1 wherein the endogenous pro-angiogenic non-peptide hormone content of the blood sample includes an elevated concentration of free T₄.

12. The method of claim 11, wherein the elevated concentration of free T₄ is greater than or equal to the upper quartile of a biologically normal T₄ range.

13. The method of claim 1, wherein the step of inducing the state of subclinical hypothyroidism, includes the step of raising thyroid stimulating hormone (TSH) to approximately greater than 3.04 μ

IU/mL, by administering to the patient an anti-thyroid agent, decreasing the patient'"'"'s production of the pro-angiogenic non-peptide hormone.

14. A method for prophylactically treating a patient with a disease susceptible to developing host resistance to angioinhibition, comprising the steps of:

inducing subclinical hypothyroidism in the patient, wherein the patient has a normal range of free T₄ present; and

administering to the patient an anti-angiogenic agent that binds to integrin α

vβ

3, an anti angiogenic agent that binds to integrin α

vβ

3 encapsulating a chemotherapeutic agent, an anti-angiogenic agent that binds to integrin α

vβ

3 encapsulating an anti-inflammatory agent or a combination of agents thereof.

15. The method of claim 14, wherein the disease susceptible to developing host resistance is selected from the group consisting of primary or metastatic tumors, adenoid carcinoma, breast cancer, kidney cancer, colon cancer, glioblastoma multiforme, head-and-neck cancer, hepatoma, lung cancer, lymphoma, melanoma, basal cell carcinoma, squamous cell carcinoma, myeloma, neuroblastaoma, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, carcinoma, stomach cancer, thyroid cancer, diabetic retinopathy, wet macular degeneration, arthritis, Parkinson'"'"'s Disease, Alzheimer'"'"'s Disease or a combination of diseases thereof.

16. The method of claim 14, wherein the step of inducing the state of subclinical hypothyroidism, includes the step of raising thyroid stimulating hormone (TSH) to greater than 3.0 μ

IU/mL, by administering an anti-thyroid agent capable of decreasing free T₄ production.

17. The method of claim 14, wherein the normal range of free T₄ present is approximately 0.8-1.8 ng/L.

18. The method of claim 14, wherein the anti-angiogenic agent that binds to integrin α

vβ

3 is tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid, or a combination thereof.

19. The method of claim 18, wherein the anti-angiogenic agent that binds to integrin α

vβ

3 is conjugated to a polymer, wherein the polymer is a nanoparticle.

20. The method of claim 19, wherein the polymer is selected from the group consisting of polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethylene glycol, methoxypolyethylene glycol-poly(lactide-co-glycolide), polyacrylic acid, polylactic acid, agarose, polyglycolide, polyethylene oxide, m-PEG, polyvinyl alcohol, polyglycolic acid, poly-L-lysine, Human Serum Albumin, carboxymethylcellulose derivatives, carboethylcellulose derivatives, carboxyhydroxypropylcellulose derivatives, hyaluronic acid, folate linked cyclodextrin, folate linked dextran, alginate, carrageenan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide, poly(lactic-co-glycolic) acid (PLGA), polylysyl glycolide, polyglycolide, polylactide, or co-polymers thereof.