# US 11,304,939 B2 · Methods for treating oral cancers

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- Number: US 11,304,939 B2
- Document ID: US11304939B2
- Status: Granted
- Kind: B2
- Application number: 15/931,613
- Filed: 2020-05-14
- Published: 2021-11-18
- Granted: 2022-04-19
- Earliest claimed: 2020-05-14
- Assignees: Chang Gung University; Chang Gung Memorial Hospital, Linkou
- Applicants: Chang Gung University; Chang Gung Memorial Hospital, Linkou
- Inventors: Chia-Yu Yang; Kai-Ping Chang; Chia-Hsun Hsieh; Chih-Ching Wu; Chun-Nan Ouyang; Chiao-Rou Liu
- Web page: https://patentgrep.com/patent/US11304939B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 33/243: Platinum; Compounds thereof
- 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

Provided herein is a method for treating an oral cancer in a subject. According to embodiments of the present disclosure, the method comprises respectively obtaining a first and a second biological samples from a lesion site and a non-lesion site of the subject; respectively measuring the expression levels of CHEK1, PIK3CA, or PIK3CD in both biological samples by qRT-PCR thereby obtaining a first and a second expression level; determining the ratio of the first to the second expression level; and administering to the subject an effective amount of a checkpoint kinase 1 inhibitor when the ratio for CHEK1 is at least 1.7 or a phosphatidylinositol 3-kinase inhibitor when the ratio for PIK3CA is at least 2.4, or when the ratio for PIK3CD is at least 3.1.

## Claims

### Claim 1

A method for treating an oral cancer in a subject, comprising,
(a) respectively obtaining a first and a second biological samples from a lesion site and a non-lesion site of the subject;
(b) respectively measuring the expression levels of a biomarker in the first and the second biological samples by quantitative reverse transcription polymerase chain reaction (qRT-PCR) thereby obtaining a first expression level and a second expression level, wherein the biomarker is CHEK1 gene, PIK3CA gene, or PIK3CD gene;
(c) determining the ratio of the first expression level to the second expression level; and
(d) administering to the subject an effective amount of a checkpoint kinase 1 inhibitor or a phosphatidylinositol 3-kinase inhibitor when the biomarker is the CHEK1 gene, and the ratio determined in the step (c) is at least 1.7; or when the biomarker is the PIK3CA gene, and the ratio determined in the step (c) is at least 2.4;
or when the biomarker is the PIK3CD gene, and the ratio determined in the step (c) is at least 3.1;
wherein in the qRT-PCR,
a primer pair of SEQ ID NOs: 1 and 2 is used for detecting the expression level of the CHEK1 gene:
a primer pair of SEQ ID NOs: 3 and 4 is used for detecting the expression level of the PIK3CA gene; and
a primer pair of SEQ ID NOs: 5 and 6 is used for detecting the expression level of the PIK3CD gene.

### Claim 2 (depends on 1)

The method of claim 1, wherein the oral cancer is oral squamous cell carcinoma (OSCC).

### Claim 3 (depends on 1)

The method of claim 1, wherein the checkpoint kinase 1 inhibitor is selected from the group consisting of,
(S)-5-(3-Fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide;
4-(((3S)-1-Azabicyclo(2.2.2)oct-3-yl)amino)-3-(1H-benzimidazol-2-yl)-6-chloroquin olin-2(1H)-one (CHIR-124);
Rabusertib;
Prexasertib;
4-(2,6-dichlorophenyl)-9-hydroxy-6-(3-(methylamino)propyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (PD-321852);
(R)-2-amino-2-cyclohexyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1, 2]diazepino[4,5,6-cd]indol-8-yl)acetamide;
(R)-6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(piperidin-3-yl)pyrazolo[1,5-a]pyrimidi n-7-amine;
(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinami de;
(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl isobutyramide;
(R)-N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nic otinamide;
(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyln icotinamide;
(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropa necarboxamide;
(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylb utanamide; and
(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopro pylacetamide.

### Claim 4 (depends on 3)

The method of claim 3, wherein the checkpoint kinase 1 inhibitor is (S)-5-(3-Fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide; Prexasertib; or
(R)-2-amino-2-cyclohexyl-N-(2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1, 2]diazepino[4,5,6-cd]indol-8-yl)acetamide.

### Claim 5 (depends on 1)

The method of claim 1, wherein the phosphatidylinositol 3-kinase inhibitor is selected from the group consisting of,
(2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxa mide;
(Z)-5-((5-(4-fluoro-2-hydroxyphenyl)furan-2-yl)methylene)thiazolidine-2,4-dione;
5-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethylene)-thiazolidine-2,4-dione;
(R)-2-(1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylamino) benzoic acid;
2-amino-N-[7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazol in;
Copanlisib;
8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinolin-2(3H)-one maleate;
Buparlisib;
Alpelisib;
(5E)-5-{[5-(4-fluorophenyl)furan-2-yl]methylidene}-1,3-thiazolidine-2,4-dione;
5-(2-Amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfon amide;
Duvelisib;
2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one;
Idelalisib;
Serabelisib;
Taselisib;
Pictilisib;
Apitolisib;
(Z)-5-((4-(pyridin-4-yl)quinolin-6-yl)methylene)thiazolidine-2,4-dione;
Omipalisib;
2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol e-4-carboxylic acid;
6-[5-[(phenylsulfonyl)amino]-3-pyridinyl]-imidazo[1,2-a]pyridine-3-carboxylic acid, ethyl ester;
2-amino-N,N-dimethyl-5-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)p yridine-3-sulfonamide;
2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one;
Dactolisib;
Perifosine;
2-Amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyr ido[2,3-d]pyrimidin-7-one;
Gedatolisib;
3-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)Phenol;
2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazi de-benzenesulfonic acid;
N-(2,3-dihydro-7,8-dimethoxyimidazo[1,2-c]quinazolin-5-yl)-3-pyridinecarboxamide;
2-[(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone;
2-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-meth yl-3-(2-methylphenyl)-4(3H)-quinazolinone;
1-(4-(3-ethyl-7-morpholino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;
Sonolisib;
(S)-2-(2-(2-Methylindolin-1-yl)-2-oxoethyl)-6-morpholinopyrimidin-4(3H)-one;
Pilaralisib;
(2S)-2-[[(2S)-3-Carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]penta noyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate;
3-(2,4-Diaminopteridin-6-yl)phenol;
Umbralisib;
5-(9-Isopropyl-8-methyl-2-morpholino-9H-purin-6-yl)pyrimidin-2-amine;
Voxtalisib; and
4,4′-(6-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2-diyl)dimor pholine.

### Claim 6 (depends on 5)

The method of claim 5, wherein the phosphatidylinositol 3-kinase inhibitor is Alpelisib;
Pictilisib; or
(Z)-5-((4-(pyridin-4-yl)quinolin-6-yl)methylene)thiazolidine-2,4-dione.

### Claim 7 (depends on 1)

The method of claim 1, further comprising administering to the subject an anti-cancer treatment selected from the group consisting of, surgery, radiotherapy, chemotherapy, immunotherapy, and a combination thereof, prior to, in conjunction with, or subsequent to the step (d).

### Claim 8 (depends on 7)

The method of claim 7, wherein the chemotherapy is conducted by administering to the subject a chemotherapeutic agent selected from the group consisting of, Bleomycin, Carboplatin, Capecitabine, Cisplatin, Docetaxel, 5-Fluorouracil (5-FU), Hydroxyurea, Methotrexate, and Paclitaxel.

### Claim 9 (depends on 8)

The method of claim 8, wherein the chemotherapeutic agent is Cisplatin.

### Claim 10 (depends on 1)

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