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WO2023230770A1 - Methods of lung adenocarcinoma treatment with non anti-luad drugs or compounds - Google Patents

Methods of lung adenocarcinoma treatment with non anti-luad drugs or compounds Download PDF

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Publication number
WO2023230770A1
WO2023230770A1 PCT/CN2022/096011 CN2022096011W WO2023230770A1 WO 2023230770 A1 WO2023230770 A1 WO 2023230770A1 CN 2022096011 W CN2022096011 W CN 2022096011W WO 2023230770 A1 WO2023230770 A1 WO 2023230770A1
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Prior art keywords
luad
drug
drugs
compounds
clinical
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French (fr)
Inventor
Jue FAN
Yan Zhang
Jinbo Zhang
Xinpeng HUANG
Jiangning Liu
Nan Fang
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Suzhou Singleron Biotechnologies Co Ltd
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Suzhou Singleron Biotechnologies Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • This disclosure generally relates to drug repurposing, and especially a list of identified approved drugs as potential anti-tumor agents against lung adenocarcinoma (LUAD) .
  • LAD lung adenocarcinoma
  • Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths in the world.
  • LUAD is a form of non-small cell lung cancer (NSCLC) , which is the most common type of lung cancer. NSCLCs account for 80%of lung malignancies, of which 50%are roughly diagnosed as adenocarcinomas.
  • LUAD is usually classified into the following several subtypes: adenocarcinoma in situ (AIS) , minimally invasive adenocarcinoma (MIA) , invasive adenocarcinoma, and variants of adenocarcinoma.
  • AIS adenocarcinoma in situ
  • MIA minimally invasive adenocarcinoma
  • MIA minimally invasive adenocarcinoma
  • variants of adenocarcinoma Despite advances in treatment strategies, the 5-year survival for LUAD patients remains low (approximately 20%) worldwide.
  • a method of treating lung adenocarcinoma can include administering to a subject in need thereof any one or a combination of at least two of drugs or compounds listed in Table 1: methyldopate, guanethidine, diphenylpyraline, tolmetin, nifenazone, Cephalothin, heptaminol, trichlormethiazide, Bucladesine, acetylcholine, imipenem, roxithromycin, butacaine, rivastigmine, ticarcillin, olmesartan, oxolamine, pirenzepine, sulfadimethoxine, tofacitinib, levalbuterol, mecamylamine, meticrane, phenylbutazone, todralazine, tranexamic acid, trimethadione, hydroquinidine, pazuflox
  • the drugs or compounds shown in Table 1 can be administered in a therapeutically effective amount.
  • the therapeutically effective amount is sufficient for inhibiting growth of LUAD cells. In some embodiments, the therapeutically effective amount is sufficient for inhibiting LUAD cell proliferation.
  • the drugs or compounds shown in Table 1 can be administered orally or via injection.
  • the present disclosure provides a method of treating LUAD by administering to a subject in need thereof any one or a combination of at least two of drugs or compounds shown in Table 1, and a convertional anti-LUAD drug (s) .
  • the aforementioned drugs lead to a number of low IC50.
  • the aforementioned drugs reduce the volume of tumor of cell line derived xenografts (CDX) model.
  • the subject is human.
  • the LUAD is NSCLC.
  • the present disclosure provides any one of the drugs listed in Table 1 for use in treating LUAD.
  • the present disclosure further provides use of any one of the drugs listed in Table 1 in treating LUAD.
  • the present disclosure further provides a method for treating LUAD in a clinical patient, comprising administering to the patient a clinically relevant dosage range of a drug or compound listed in Table 1.
  • the drug or compound is administered at a therapeutically effective concentration.
  • the administration of said drug or compound reduces the volume of LUAD tumor in clinical patients.
  • the present disclosure further provides a combination therapy to treat a LUAD patient to control the development of tumor, comprising administering a clinical range of a non-anti-LUAD drug proposed to be repurposed with a conventional anti-LUAD drug to the patient, wherein the combination of said non-anti-LUAD drug and said conventional anti-LUAD drug is administered at a clinically relevant dosage.
  • said non-anti-LUAD drug provides synergy to said conventional anti-LUAD drug.
  • the non-anti-LUAD drug is selected from the group consisting of methyldopate, guanethidine, diphenylpyraline, tolmetin, nifenazone, Cephalothin, heptaminol, trichlormethiazide, Bucladesine, acetylcholine, imipenem, roxithromycin, butacaine, rivastigmine, ticarcillin, olmesartan, oxolamine, pirenzepine, sulfadimethoxine, tofacitinib, levalbuterol, mecamylamine, meticrane, phenylbutazone, todralazine, tranexamic acid, trimethadione, hydroquinidine, pazufloxacin, bretylium, almitrine, chloroprocaine, hydroflumethiazide, deslanoside, Fomepizole, bicyclo
  • the present disclosure further provides a pharmaceutical combination comprising any one or a combination of at least two of the drugs listed in Table 1, and a conventional anti-LUAD drug.
  • the human LUAD cell lines were sourced from commercial vendors. The cancer cells were cultured in RPMI 1640 Medium, supplemented with 10%FBS and 1%penicillin/streptomycin, and were maintained in an incubator at 37 °C and 5%CO 2 . Then the human LUAD cell lines cells were each plated at 5,000 cells per 100 ⁇ l AR-5 medium (ACL4 media with 5%FBS) per well in 96-well plates. For some of screened drugs with definite IC 50 s in public datasets, cells were treated with them in considerate IC 50 s concentrations. Cells were collected on day 0 (control) or after 48 h of treatment. For others, cells per well were treated with those drugs at their indicated doses as a series of concentrations. After three or five days of treatment cells were collected. The cell viability of the samples was used to assess drugs sensitivity.
  • mice Male BALB/c nude mice were housed in a specific pathogen-free facility. In total, 1 ⁇ 10 7 human LUAD cell lines were suspended in PBS and injected subcutaneously into the right flank of each mouse to generate xenograft tumors. When the tumor volume reached an average of ⁇ 100 mm 3 , mice were randomly divided into four groups for each drug: the DMSO group and the drug treated (three different low, medium, and high concentrations of the drug) group; each group had three technical replicate samples. The mice in each group were treated with drug or DMSO through oral gavage or injection. The oral gavage or injection repeated once a day for two weeks. The tumor size (length and width) was measured using a digital caliper every other day to monitor the growth of the tumor. The formula was used to evaluate tumor volume at indicated time points: 1/2 ⁇ L ⁇ W 2 , with L denoting the longest tumor diameter and W is the shortest. Mouse was weighed every other day.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method of treating lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), is provided. This method of treating LUAD can include: providing non anti-LUAD drugs or compounds provided herein to a subject having LUAD.

Description

METHODS OF LUNG ADENOCARCINOMA TREATMENT WITH NON ANTI-LUAD DRUGS OR COMPOUNDS TECHNICAL FIELD
This disclosure generally relates to drug repurposing, and especially a list of identified approved drugs as potential anti-tumor agents against lung adenocarcinoma (LUAD) .
BACKGROUD
Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths in the world. LUAD is a form of non-small cell lung cancer (NSCLC) , which is the most common type of lung cancer. NSCLCs account for 80%of lung malignancies, of which 50%are roughly diagnosed as adenocarcinomas. LUAD is usually classified into the following several subtypes: adenocarcinoma in situ (AIS) , minimally invasive adenocarcinoma (MIA) , invasive adenocarcinoma, and variants of adenocarcinoma. Despite advances in treatment strategies, the 5-year survival for LUAD patients remains low (approximately 20%) worldwide. Nowadays, drug repositioning, repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration, is considered as an cost-effective and pragmatic way to improve lung cancer therapy. Accordingly, it would be important to accelerate drug discovery and approval by drug repurposing, which can help improve outcomes for patients affected by lung adenocarcinoma.
SUMMARY
In an aspect, a method of treating lung adenocarcinoma (LUAD) is provided. The method of treating LUAD can include administering to a subject in need thereof any one or a combination of at least two of drugs or compounds listed in Table 1: methyldopate, guanethidine, diphenylpyraline, tolmetin, nifenazone, Cephalothin, heptaminol, trichlormethiazide, Bucladesine, acetylcholine, imipenem, roxithromycin, butacaine, rivastigmine, ticarcillin, olmesartan, oxolamine, pirenzepine, sulfadimethoxine, tofacitinib, levalbuterol, mecamylamine, meticrane, phenylbutazone, todralazine, tranexamic acid, trimethadione, hydroquinidine, pazufloxacin, bretylium, almitrine, chloroprocaine, hydroflumethiazide, deslanoside, Fomepizole, bicyclol, pretomanid, nedocromil, irbesartan, riboflavin-5-phosphate, succinic-acid, gallopamil, boceprevir, teneligliptin, trelagliptin, alogliptin, anagliptin, carbenoxolone, dicoumarol, azosemide, piretanide, garenoxacin, pefloxacin, L-citrulline, aprindine, flunarizine, perphenazine, anisindione, quinidine, inosine, Aminocaproic acid, and trometamol.
The drugs or compounds shown in Table 1 can be administered in a therapeutically effective  amount. In some embodiments, the therapeutically effective amount is sufficient for inhibiting growth of LUAD cells. In some embodiments, the therapeutically effective amount is sufficient for inhibiting LUAD cell proliferation.
Table 1. Candidate drugs for LUAD treatment.
methyldopate olmesartan almitrine alogliptin
guanethidine oxolamine chloroprocaine anagliptin
diphenylpyraline pirenzepine hydroflumethiazide carbenoxolone
tolmetin sulfadimethoxine deslanoside dicoumarol
nifenazone tofacitinib Fomepizole azosemide
Cephalothin levalbuterol bicyclol piretanide
heptaminol mecamylamine pretomanid garenoxacin
trichlormethiazide meticrane nedocromil pefloxacin
Bucladesine phenylbutazone irbesartan L-citrulline
acetylcholine todralazine riboflavin-5-phosphate aprindine
imipenem tranexamic acid succinic-acid flunarizine
roxithromycin trimethadione gallopamil perphenazine
butacaine hydroquinidine boceprevir anisindione
rivastigmine pazufloxacin teneligliptin quinidine
ticarcillin bretylium trelagliptin inosine
Aminocaproic acid trometamol    
In some embodiments, the drugs or compounds shown in Table 1 can be administered orally or via injection.
In an aspect, the present disclosure provides a method of treating LUAD by administering to a subject in need thereof any one or a combination of at least two of drugs or compounds shown in Table 1, and a convertional anti-LUAD drug (s) .
In some embodiments, the aforementioned drugs lead to a number of low IC50.
In some embodiments, the aforementioned drugs reduce the volume of tumor of cell line derived xenografts (CDX) model.
In some embodiments, the subject is human.
In some embodiments, the LUAD is NSCLC.
The following descriptions and claims give a better understanding of the invention’s features, aspects and advantages.
DETAILED DESCRIPTION
The present disclosure provides any one of the drugs listed in Table 1 for use in treating  LUAD.
The present disclosure further provides use of any one of the drugs listed in Table 1 in treating LUAD.
The present disclosure further provides a method for treating LUAD in a clinical patient, comprising administering to the patient a clinically relevant dosage range of a drug or compound listed in Table 1.
In an embodiment, the drug or compound is administered at a therapeutically effective concentration.
In an embodiment, the administration of said drug or compound reduces the volume of LUAD tumor in clinical patients.
The present disclosure further provides a combination therapy to treat a LUAD patient to control the development of tumor, comprising administering a clinical range of a non-anti-LUAD drug proposed to be repurposed with a conventional anti-LUAD drug to the patient, wherein the combination of said non-anti-LUAD drug and said conventional anti-LUAD drug is administered at a clinically relevant dosage.
In an embodiment, said non-anti-LUAD drug provides synergy to said conventional anti-LUAD drug.
In an embodiment, the non-anti-LUAD drug is selected from the group consisting of methyldopate, guanethidine, diphenylpyraline, tolmetin, nifenazone, Cephalothin, heptaminol, trichlormethiazide, Bucladesine, acetylcholine, imipenem, roxithromycin, butacaine, rivastigmine, ticarcillin, olmesartan, oxolamine, pirenzepine, sulfadimethoxine, tofacitinib, levalbuterol, mecamylamine, meticrane, phenylbutazone, todralazine, tranexamic acid, trimethadione, hydroquinidine, pazufloxacin, bretylium, almitrine, chloroprocaine, hydroflumethiazide, deslanoside, Fomepizole, bicyclol, pretomanid, nedocromil, irbesartan, riboflavin-5-phosphate, succinic-acid, gallopamil, boceprevir, teneligliptin, trelagliptin, alogliptin, anagliptin, carbenoxolone, dicoumarol, azosemide, piretanide, garenoxacin, pefloxacin, L-citrulline, aprindine, flunarizine, perphenazine, anisindione, quinidine, inosine, Aminocaproic acid, and trometamol.
The present disclosure further provides a pharmaceutical combination comprising any one or a combination of at least two of the drugs listed in Table 1, and a conventional anti-LUAD drug.
Materials and methods
Experiments on lung cancer cell lines
Validation experiments of drug sensitivity on treating NSCLC were conducted. The human LUAD cell lines were sourced from commercial vendors. The cancer cells were cultured in RPMI  1640 Medium, supplemented with 10%FBS and 1%penicillin/streptomycin, and were maintained in an incubator at 37 ℃ and 5%CO 2. Then the human LUAD cell lines cells were each plated at 5,000 cells per 100μl AR-5 medium (ACL4 media with 5%FBS) per well in 96-well plates. For some of screened drugs with definite IC 50s in public datasets, cells were treated with them in considerate IC 50s concentrations. Cells were collected on day 0 (control) or after 48 h of treatment. For others, cells per well were treated with those drugs at their indicated doses as a series of concentrations. After three or five days of treatment cells were collected. The cell viability of the samples was used to assess drugs sensitivity.
Secondly, we did the experiments with 4 groups for each drug: control, three drug concentrations (represent three different low, medium, and high concentrations of the drug) on the human LUAD cell lines. Each group had three technical replicate samples. After 24 hours, all the samples were used to do the RNA-Seq experiments and the downstream analysis.
Animal model experiments
Male BALB/c nude mice were housed in a specific pathogen-free facility. In total, 1×10 7 human LUAD cell lines were suspended in PBS and injected subcutaneously into the right flank of each mouse to generate xenograft tumors. When the tumor volume reached an average of ～ 100 mm 3, mice were randomly divided into four groups for each drug: the DMSO group and the drug treated (three different low, medium, and high concentrations of the drug) group; each group had three technical replicate samples. The mice in each group were treated with drug or DMSO through oral gavage or injection. The oral gavage or injection repeated once a day for two weeks. The tumor size (length and width) was measured using a digital caliper every other day to monitor the growth of the tumor. The formula was used to evaluate tumor volume at indicated time points: 1/2×L×W 2, with L denoting the longest tumor diameter and W is the shortest. Mouse was weighed every other day.

Claims (9)

  1. A method of using candidate drugs/compounds to treat lung adenocarcinoma (LUAD) , comprising:
    a) screening a list of drugs/compounds, wherein the list includes a plurality of approved drugs or compounds which have not been used against LUAD to date of this disclosure;
    b) identifying several drugs/compounds from the list for their ability to reduce tumor volume, perform cancer cell killing or inhibit tumor growth in mouse model with not strongly interfering normal physiology function and little side effects;
    c) the purpose and application of identified candidate drugs/compounds on LUAD treatment;
    d) the concentration/dose of identified candidate drugs/compounds used in clinical settings.
  2. The method according to claim 1, wherein the mouse model and tumor specifically refers to LUAD cancer model and LUAD tumor respectively; wherein mouse models of cancer refers to mouse xenograft models (cell line derived xenografts (CDX) model) .
  3. The method of according to claim 1, wherein the dosage of drugs/compounds used in clinical is dependent on clinical experiments.
  4. A method of treating LUAD in a clinical patient, comprising administering to the patient a clinical relevant dosage range of a drug or compound, wherein the drug or compound is any one or a combination of at least two selected from the group consisting of methyldopate, guanethidine, diphenylpyraline, tolmetin, nifenazone, Cephalothin, heptaminol, trichlormethiazide, Bucladesine, acetylcholine, imipenem, roxithromycin, butacaine, rivastigmine, ticarcillin, olmesartan, oxolamine, pirenzepine, sulfadimethoxine, tofacitinib, levalbuterol, mecamylamine, meticrane, phenylbutazone, todralazine, tranexamic acid, trimethadione, hydroquinidine, pazufloxacin, bretylium, almitrine, chloroprocaine, hydroflumethiazide, deslanoside, Fomepizole, bicyclol, pretomanid, nedocromil, irbesartan, riboflavin-5-phosphate, succinic-acid, gallopamil, boceprevir, teneligliptin, trelagliptin, alogliptin, anagliptin, carbenoxolone, dicoumarol, azosemide, piretanide, garenoxacin, pefloxacin, L-citrulline, aprindine, flunarizine, perphenazine, anisindione, quinidine, inosine, Aminocaproic acid, and trometamol.
  5. The method of claim 4, wherein said clinically relevant dosage range is about micromolar to about nanomolar.
  6. The method of claim 4, wherein the administration of said drug or compound reduces the volume of LUAD tumor in clinical patients.
  7. A combination therapy to treat a LUAD patient to control the development of tumor, comprising administering a clinical range of a non-anti-LUAD drug proposed to be repurposed with a conventional anti-LUAD drug to the patient, wherein the combination of said  non-anti-LUAD drug and said conventional anti-LUAD drug is administered at a clinically relevant dosage.
  8. The combinational therapy according to claim 7, wherein said non-anti-LUAD drug provides synergy to said conventional anti-LUAD drug.
  9. The combinational therapy according to claim 7, wherein the non-anti-LUAD drug is selected from the group consisting of methyldopate, guanethidine, diphenylpyraline, tolmetin, nifenazone, Cephalothin, heptaminol, trichlormethiazide, Bucladesine, acetylcholine, imipenem, roxithromycin, butacaine, rivastigmine, ticarcillin, olmesartan, oxolamine, pirenzepine, sulfadimethoxine, tofacitinib, levalbuterol, mecamylamine, meticrane, phenylbutazone, todralazine, tranexamic acid, trimethadione, hydroquinidine, pazufloxacin, bretylium, almitrine, chloroprocaine, hydroflumethiazide, deslanoside, Fomepizole, bicyclol, pretomanid, nedocromil, irbesartan, riboflavin-5-phosphate, succinic-acid, gallopamil, boceprevir, teneligliptin, trelagliptin, alogliptin, anagliptin, carbenoxolone, dicoumarol, azosemide, piretanide, garenoxacin, pefloxacin, L-citrulline, aprindine, flunarizine, perphenazine, anisindione, quinidine, inosine, Aminocaproic acid, and trometamol.
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