# US 8,771,754 B2 · Use of GSK3 inhibitors in combination with radiation therapies

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- Number: US 8,771,754 B2
- Document ID: US8771754B2
- Status: Granted
- Kind: B2
- Application number: 11/663,314
- Filed: 2005-09-19
- Published: 2009-02-12
- Granted: 2014-07-08
- Earliest claimed: 2004-09-17
- Assignees: Vanderbilt University
- Applicants: Dennis E. Hallahan
- Inventors: Dennis E. Hallahan
- Web page: https://patentgrep.com/patent/US8771754B2

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The presently disclosed subject matter relates generally to the fields of molecular biology and medicine. More particularly, it concerns methods involving the use of GSK3 inhibitors in combination with radiation therapies. In some embodiments, administration of a GSK3 inhibitor to a subject results in an amelioration of cognitive decline, toxicity to vascular endothelial cells, and/or neuron death associated with radiation therapy alone.

## Claims

### Claim 1

A method for treating a hyperproliferative disease in a subject comprising administering radiation therapy in combination with a pharmaceutical composition comprising an inhibitor of glycogen synthase kinase 3 (GSK3) comprising lithium or a pharmaceutically acceptable salt thereof to the subject, wherein the inhibitor of GSK3 is administered to the subject prior to and during administration of the radiation therapy, and in an amount and via a route effective to protect a cell selected from the group consisting of a neuron, a vascular endothelial cell, a salivary gland cell, a gastrointestinal tract cell, a lung cell, and a liver cell from radiation-induced apoptosis.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject is a mammal.

### Claim 3 (depends on 2)

The method of claim 2, wherein the mammal is a human.

### Claim 4 (depends on 1)

The method of claim 1, wherein the GSK3 inhibitor is administered in a pharmaceutically acceptable carrier, diluent, or vehicle.

### Claim 5 (depends on 1)

The method of claim 1, wherein the GSK3 inhibitor is administered to the subject intranasally, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, via inhalation, via injection, via infusion, via continuous infusion, via localized perfusion to a tumor, by bathing target cells directly, via a catheter, via a lavage, in a creme, in a lipid composition, or by any combination of the forgoing.

### Claim 6 (depends on 5)

The method of claim 5, wherein the tumor comprises a cancerous tumor.

### Claim 7 (depends on 6)

The method of claim 6, wherein the tumor comprises a brain tumor.

### Claim 8 (depends on 6)

The method of claim 6, wherein the tumor comprises a lung tumor.

### Claim 9 (depends on 1)

The method of claim 1, wherein the hyperproliferative disease is selected from the group consisting of a benign tumor, an arteriovenous malformation, a neuroma, a meningioma, a schwanoma, an adenoma, a glioma, and combinations thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein the neuroma comprises an acoustic neuroma or an optic neuroma.

### Claim 11 (depends on 9)

The method of claim 9, wherein the adenoma comprises a pituitary adenoma.

### Claim 12 (depends on 9)

The method of claim 9, wherein the glioma comprises an optic glioma.

### Claim 13 (depends on 9)

The method of claim 9, wherein the benign tumor is selected from the group consisting of a brain tumor, a spinal cord tumor, an eye tumor, and a lung tumor.

### Claim 14 (depends on 1)

The method of claim 1, wherein the hyperproliferative disease comprises cancer.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is selected from the group consisting of lung cancer, prostate cancer, ovarian cancer, testicular cancer, brain cancer, skin cancer, colon cancer, gastric cancer, esophageal cancer, tracheal cancer, head and neck cancer, pancreatic cancer, liver cancer, breast cancer, ovarian cancer, lymphoid cancer, leukemia, cervical cancer, vulvar cancer, and cancer of the eye.

### Claim 16 (depends on 15)

The method of claim 15, wherein the cancer comprises brain cancer.

### Claim 17 (depends on 15)

The method of claim 15, wherein the cancer comprises lung cancer.

### Claim 18 (depends on 14)

The method of claim 14, wherein the radiation therapy comprises cranial radiation therapy.

### Claim 19 (depends on 14)

The method of claim 14, wherein the administering comprises administering a sufficient amount of the GSK3 inhibitor to result in a reduction in toxicity associated with the radiation therapy to a neuron.

### Claim 20 (depends on 19)

The method of claim 19, wherein the neuron comprises a neuron of the central nervous system.

### Claim 21 (depends on 20)

The method of claim 20, wherein the neuron is a hippocampal neuron.

### Claim 22 (depends on 19)

The method of claim 19, wherein the neuron comprises a neuron of the peripheral nervous system.

### Claim 23 (depends on 19)

The method of claim 19, wherein the toxicity comprises neuron death.

### Claim 24 (depends on 19)

The method of claim 19, wherein the toxicity comprises apoptosis.

### Claim 25 (depends on 18)

The method of claim 18, wherein the administering comprises administering a sufficient amount of the GSK3 inhibitor to result in a reduction in cognitive decline of the subject associated with the cranial radiation therapy.

### Claim 26 (depends on 18)

The method of claim 18, wherein the administering comprises a sufficient amount of the GSK3 inhibitor to result in a reduction in toxicity associated with the cranial radiation therapy to non-neuronal cells.

### Claim 27 (depends on 26)

The method of claim 26, wherein the non-neuronal cells are vascular endothelial cells.

### Claim 28 (depends on 26)

The method of claim 26, wherein the non-neuronal cells are salivary gland cells, gastrointestinal tract cells, lung cells, liver cells, or vascular endothelial cells.

### Claim 29 (depends on 28)

The method of claim 28, wherein the toxicity comprises death of the cells.

### Claim 30 (depends on 28)

The method of claim 28, wherein the toxicity comprises apoptosis of the cells.

### Claim 31 (depends on 28)

The method of claim 28, wherein the reduction of toxicity comprises an elimination of toxicity.

### Claim 32 (depends on 1)

The method of claim 1, further comprising administering a second pharmaceutical composition.

### Claim 33 (depends on 32)

The method of claim 32, wherein the second pharmaceutical composition comprises an anti-cancer composition.

### Claim 34 (depends on 1)

The method of claim 1, wherein the inhibitor of GSK3 is administered to the subject beginning about 7 days prior to the administration of the radiation therapy.

### Claim 35 (depends on 34)

The method of claim 34, wherein the inhibitor of GSK3 is administered daily to the subject beginning about 7 days prior to the administration of the radiation therapy.