WO2022252044A1 - Drug repurposing to treat primary lung adenocarcinoma based on deep embeddings of single-cell sequencing analysis - Google Patents

Drug repurposing to treat primary lung adenocarcinoma based on deep embeddings of single-cell sequencing analysis Download PDF

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WO2022252044A1
WO2022252044A1 PCT/CN2021/097369 CN2021097369W WO2022252044A1 WO 2022252044 A1 WO2022252044 A1 WO 2022252044A1 CN 2021097369 W CN2021097369 W CN 2021097369W WO 2022252044 A1 WO2022252044 A1 WO 2022252044A1
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luad
drug
drugs
clinical
tumor
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PCT/CN2021/097369
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French (fr)
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Xinlei ZHAO
Jue FAN
Yan Zhang
Nan Fang
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Suzhou Singleron Biotechnologies Co., Ltd.
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Priority to PCT/CN2022/093797 priority patent/WO2022252994A1/en
Publication of WO2022252044A1 publication Critical patent/WO2022252044A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

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  • This disclosure generally relates to drug repurposing, and especially a list of identified FDA approved drugs as potential anti-tumor agents against lung adenocarcinoma (LUAD) .
  • LAD lung adenocarcinoma
  • This disclosure provides a method of utilizing FDA approved non-anti-LUAD drugs to treat primary LUAD in clinically relevant range.
  • a few drugs, originally not approved for primary LUAD are screened out of all FDA approved drugs, and are evaluated for their clinical potentials on treatment of LUAD by in-silico methods, as well as in vitro and in vivo experiments.
  • the anticancer activity of these drugs is tested via various metric including but not limited to IC 50 , and tumor volume reduction.
  • the present disclosure provides any one of the drugs listed in Table 1 for use in treating primary LUAD.
  • the present disclosure provides use of any one of the drugs listed in Table 1 in treating primary LUAD.
  • the present disclosure 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.
  • this disclosure also provides a possibly precise or combinational therapy to a patient with drug resistance or highly heterogeneous tumor.
  • the therapy may consist of candidate drugs listed in Table 1 with a conventional anti-LUAD tumor drug.
  • the aforementioned drugs lead to a number of low IC 50 .
  • the aforementioned drugs reduce the volume of tumor of PDX model.
  • Figure 1 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 2 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 3 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 4 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 5 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 6 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 7 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 8 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 9 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 10 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 11 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 12 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 13 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 14 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 15 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 16 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 17 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 18 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 19 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 20 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 21 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 22 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 23 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 24 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 25 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 26 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 27 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 28 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 29 Dose response curve of a potential drug which can be used to treat primary LUAD.
  • Figure 30 The IC 50 and AUC (area under the dose response curve) of drugs on lung cancer cell lines, corresponding to curves of Figures 1-29.
  • the present disclosure provides any one of the drugs listed in Table 1 for use in treating primary LUAD.
  • the present disclosure further provides use of any one of the drugs listed in Table 1 in treating primary 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 concentration as listed in Table 2.
  • Drug name Concentration Drug name Concentration BMS-536924 0.01nM ⁇ 1uM AT-7519 0.1nM ⁇ 1mM GSK1904529A 1nm ⁇ 1mM PHA-793887 1nM ⁇ 1mM AZD6482 0.1uM ⁇ 1mM BMS-754807 1nM ⁇ 1mM PI-103 1nM ⁇ 1mM Linsitinib (OSI-906) 1nM ⁇ 1mM Dacinostat (LAQ824) 0.1nM ⁇ 100uM Dactolisib (NVP-BEZ235) 0.1nM ⁇ 10uM TW-37 10nM ⁇ 1mM AZD8835 0.1uM ⁇ 1mM Ciclopirox 1nM ⁇ 1mM Idelalisib (CAL-101) 0.1uM ⁇ 10mM
  • the drug or compound is administered through, for example but not limited to, approved routes of drug administration, such as through oral for Dactolisib and Ciclopirox.
  • 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 BMS-536924, GSK1904529A, AZD6482, PI-103, Dacinostat (also known as LAQ824) , TW-37, Ciclopirox, Tosedostat, Niclosamide, Palbociclib (also known as PD-0332991) , PF-562271, Belinostat, NVP-ADW742, Ribociclib, ABT-737, AT-7519, PHA-793887, BMS-754807, Linsitinib (also known as OSI-906) , Dactolisib (also known as NVP-BEZ235) , AZD8835, Idelalisib (also known as CAL-101) , Voxtalisib (also known as XL765) , Panobinostat, Vorinostat, ACY-1215 (also known as Ricolinostat) , Alpelisib, GDC-
  • the present disclosure further provides a pharmaceutical combination comprising any one or a combinationof at least two of the drugs listed in Table 1, and a conventional anti-LUAD drug.
  • drugs are firstly selected that have dose response curves on lung cancer cell lines based on data from GDSC and CTRPv2 (Table 1) .
  • these drugs/compounds have at least one dose response curve in GDSC or CTRPv2 and showed to inhibit proliferation and viability of cultured lung cancer cell lines.
  • Figures 1-29 shows 29 dose response curves of 29 drugs on variable lung cancer cell lines
  • Figure 30 refers to the IC 50 and AUC of drugs on lung cancer cell lines corresponding to Figures 1-29.
  • Lung cancer cell lines are sourced from commercial vendors. Cancer cells are cultured in RPMI 1640 Medium, supplemented with 10%FBS and 1%penicillin/streptomycin, and are maintained in an incubator at 37 °C and 5%CO 2 . Then lung cancer cell line cells are 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.
  • cells per well are treated with those drugs at their indicated doses as a series of concentrations. After three or five days of treatment cells are collected. The cell viability of the samples is used to assess drugs sensitivity. Finally, drugs with the low cell viability and clinical concentrations about ⁇ M to nM are selected to proceed in PDX model experiments.
  • NSCLC PDX models derived from patients are purchased. Animals are randomly divided into the control and drug-perturbation groups. Then animals are given injections of 50 ml DMSO (vehicle control) in the control group or variable amounts of candidate drugs every 3 days for 2 weeks. Tumor size is measured using digital calipers every 3 days. Tumor volume is determined by calculating (length x width2) /2. Growth curves and survival curves are generated to evaluate medicine efficacy.

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Abstract

Disclosed herein is the discovery of the repurposed drugs that could be used to clinically treat patients of primary lung adenocarcinoma (LUAD) based on single-cell sequencing analysis and experimental validation. These repurposed drugs can be used either alone or in combination with other known anti-LUAD drugs to treat patients that may develop or already have developed drug resistance.

Description

DRUG REPURPOSING TO TREAT PRIMARY LUNG ADENOCARCINOMA BASED ON DEEP EMBEDDINGS OF SINGLE-CELL SEQUENCING ANALYSIS TECHNICAL FIELD
This disclosure generally relates to drug repurposing, and especially a list of identified FDA approved drugs as potential anti-tumor agents against lung adenocarcinoma (LUAD) .
BACKGROUD
This section introduces respects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
It is widely recognized that tumor is a heterogenetic disease whatever inter-and even intra-patients. LUAD, as one of the cancers with high mortality, increasingly becomes a serious threat to the personal health worldwide. Moreover, the development of new anti-LUAD drugs is time and also cost inefficient. Therefore, novel drugs, new targets and approaches to develop them are urgently needed. Drug repurposing shows advantages of shorter development time, lower cost and lower toxicity risk comparing to de novo drug discovery, and it has already resulted in success in other disease areas, such as asthma. Single-cell sequencing technology pave the way for realizing personalized medicine while revealing the intra-and inter-patient tumor heterogeneity. Given crucial problems (such as poor prognosis) posed by heterogeneous and drug-resistant cancer cells, there is an unmet need for methods for promptly uncovering new therapies.
SUMMARY
This disclosure provides a method of utilizing FDA approved non-anti-LUAD drugs to treat primary LUAD in clinically relevant range. In particularly, a few drugs, originally not approved for primary LUAD, are screened out of all FDA approved drugs, and are evaluated for their clinical potentials on treatment of LUAD by in-silico methods, as well as in vitro and in vivo experiments. The anticancer activity of these drugs is tested via various metric including but not limited to IC 50, and tumor volume reduction.
Candidate repurposing drugs have not been approved for LUAD treatment are shown in Table 1.
Table 1 Candidate drugs for LUAD
Figure PCTCN2021097369-appb-000001
In another aspect, the present disclosure provides any one of the drugs listed in Table 1 for use in treating primary LUAD.
In another aspect, the present disclosure provides use of any one of the drugs listed in Table 1 in treating primary LUAD.
In another aspect, the present disclosure 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 addition, this disclosure also provides a possibly precise or combinational therapy to a patient with drug resistance or highly heterogeneous tumor. The therapy may consist of candidate drugs listed in Table 1 with a conventional anti-LUAD tumor drug.
In some embodiment, the aforementioned drugs lead to a number of low IC 50.
In some embodiment, the aforementioned drugs reduce the volume of tumor of PDX model.
The following figures, associated descriptions and claims give a better understanding of the invention’s features, aspects and advantages.
BRIEF DESCRITION OF THE FIGURES
Figure 1: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 2: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 3: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 4: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 5: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 6: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 7: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 8: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 9: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 10: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 11: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 12: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 13: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 14: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 15: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 16: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 17: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 18: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 19: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 20: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 21: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 22: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 23: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 24: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 25: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 26: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 27: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 28: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 29: Dose response curve of a potential drug which can be used to treat primary LUAD.
Figure 30: The IC 50 and AUC (area under the dose response curve) of drugs on lung cancer cell lines, corresponding to curves of Figures 1-29.
DETAILED DESCRIPTION
The present disclosure provides any one of the drugs listed in Table 1 for use in treating primary LUAD.
The present disclosure further provides use of any one of the drugs listed in Table 1 in treating primary 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 concentration as listed in Table 2.
Table 2. Clinically recommended concentration ranges of drugs aforementioned in Table 1.
Drug name Concentration Drug name Concentration
BMS-536924 0.01nM～1uM AT-7519 0.1nM～1mM
GSK1904529A 1nm～1mM PHA-793887 1nM～1mM
AZD6482 0.1uM～1mM BMS-754807 1nM～1mM
PI-103 1nM～1mM Linsitinib (OSI-906) 1nM～1mM
Dacinostat (LAQ824) 0.1nM～100uM Dactolisib (NVP-BEZ235) 0.1nM～10uM
TW-37 10nM～1mM AZD8835 0.1uM～1mM
Ciclopirox 1nM～1mM Idelalisib (CAL-101) 0.1uM～10mM
Tosedostat 10nM～1mM Voxtalisib (XL765) 1nM～10mM
Niclosamide 10nM～1mM Panobinostat 0.1nM～100uM
Palbociclib (PD-0332991) 1nM～1mM Vorinostat 10nM～100uM
PF-562271 1nM～100uM ACY-1215 (Ricolinostat) 10nM～100uM
Belinostat 1nM～100uM Alpelisib 0.01uM～1mM
NVP-ADW742 10nM～1mM GDC-0941 1nm～1mM
Ribociclib 0.01nM～100uM Ouabain 0.1nM～100uM
ABT-737 1nm～1mM NVP-BEZ235 0.01nM～1mM
Note: concentration: nM=nmol/L; uM=umol/L; mM=mmol/L
In an embodiment, the drug or compound is administered through, for example but not limited to, approved routes of drug administration, such as through oral for Dactolisib and Ciclopirox.
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 BMS-536924, GSK1904529A, AZD6482, PI-103, Dacinostat (also known as LAQ824) , TW-37, Ciclopirox, Tosedostat, Niclosamide, Palbociclib (also known as PD-0332991) , PF-562271, Belinostat, NVP-ADW742, Ribociclib, ABT-737, AT-7519, PHA-793887, BMS-754807, Linsitinib (also known as OSI-906) , Dactolisib (also known as NVP-BEZ235) , AZD8835, Idelalisib (also known as CAL-101) , Voxtalisib (also known as XL765) , Panobinostat, Vorinostat, ACY-1215 (also known as Ricolinostat) , Alpelisib, GDC-0941, Ouabain, and NVP-BEZ235.
The present disclosure further provides a pharmaceutical combination comprising any one or a combinationof at least two of the drugs listed in Table 1, and a conventional anti-LUAD drug.
In this disclosure, drugs are firstly selected that have dose response curves on lung cancer cell lines based on data from GDSC and CTRPv2 (Table 1) . Specifically, these drugs/compounds have at least one dose response curve in GDSC or CTRPv2 and showed to inhibit proliferation and viability of cultured lung cancer cell lines. Especially, Figures 1-29 shows 29 dose response curves of 29 drugs on variable lung cancer cell lines, and Figure 30 refers to the IC 50 and AUC of drugs on lung cancer cell lines corresponding to Figures 1-29.
Next, we filtered the candidate repurposing drugs based on their reversibility of abnormal changes from normal to cancer. Based on more than 200 single cell RNA-seq data of LUAD  patients, we annotated and compared the differences between tumor cells and normal epithelial cells. Drug which reverse the cancer cells to a near normal state were kept as candidate repurposing drugs. Also, drugs whose targets were abnormally activated in cancer cells were kept as additional candidate repurposing drugs.
Materials and methods
Experiments on lung cancer cell lines
Validation experiments of drug sensitivity on treating NSCLC are conducted. Lung cancer cell lines are sourced from commercial vendors. Cancer cells are cultured in RPMI 1640 Medium, supplemented with 10%FBS and 1%penicillin/streptomycin, and are maintained in an incubator at 37 ℃ and 5%CO 2. Then lung cancer cell line cells are 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 are treated with those drugs at their indicated doses as a series of concentrations. After three or five days of treatment cells are collected. The cell viability of the samples is used to assess drugs sensitivity. Finally, drugs with the low cell viability and clinical concentrations about μM to nM are selected to proceed in PDX model experiments.
Animal model experiments
NSCLC PDX models derived from patients are purchased. Animals are randomly divided into the control and drug-perturbation groups. Then animals are given injections of 50 ml DMSO (vehicle control) in the control group or variable amounts of candidate drugs every 3 days for 2 weeks. Tumor size is measured using digital calipers every 3 days. Tumor volume is determined by calculating (length x width2) /2. Growth curves and survival curves are generated to evaluate medicine efficacy.

Claims (11)

  1. A method of using candidate drugs/compounds to treat primary lung adenocarcinoma (LUAD) , comprising:
    a) screening a list of drugs/compounds, wherein the list includes a plurality of FDA approved drugs or small molecule compounds which have not been used against primary 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 primary LUAD treatment;
    d) the concentration/dose of identified candidate drugs/compounds used in clinical settings.
  2. The method according to claim 1, wherein the list of drugs/compounds are screened selected from GDSC and CTRPv2 datasets and have at least one dose response curve on lung cancer cell lines in the two datasets; and these drugs have not been tested and used in mouse cancer model of LUAD and in clinical LUAD patients.
  3. 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, either by xenotransplantation of cancer cell lines or patient-derived LUAD tumor xenografts (PDXs) in immune-deficient mice.
  4. The method of according to claim 1, wherein the dosage of drugs/compounds used in clinical is dependent on clinical experiments.
  5. 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 BMS-536924, GSK1904529A, AZD6482, PI-103, Dacinostat, TW-37, Ciclopirox, Tosedostat, Niclosamide, Palbociclib, PF-562271, Belinostat, NVP-ADW742, Ribociclib, ABT-737, AT-7519, PHA-793887, BMS-754807, Linsitinib, Dactolisib, AZD8835, Idelalisib, Voxtalisib, Panobinostat, Vorinostat, ACY-1215, Alpelisib, GDC-0941, Ouabain, and NVP-BEZ235.
  6. The method of claim 5, wherein said clinically relevant dosage range is about micromolar to about nanomolar.
  7. The method of claim 5, wherein the administration of Dactolisib is through oral; and the the administration of Ciclopirox is through oral.
  8. The method of claim 5, wherein the administration of said drug or compound reduces the volume of LUAD tumor in clinical patients.
  9. 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.
  10. The combinational therapy according to claim 9, wherein said non-anti-LUAD drug provides synergy to said conventional anti-LUAD drug.
  11. The combinational therapy according to claim 9, wherein the non-anti-LUAD drug is selected from the group consisting of BMS-536924, GSK1904529A, AZD6482, PI-103, Dacinostat, TW-37, Ciclopirox, Tosedostat, Niclosamide, Palbociclib, PF-562271, Belinostat, NVP-ADW742, Ribociclib, ABT-737, AT-7519, PHA-793887, BMS-754807, Linsitinib, Dactolisib, AZD8835, Idelalisib, Voxtalisib, Panobinostat, Vorinostat, ACY-1215, Alpelisib, GDC-0941, Ouabain, and NVP-BEZ235.
PCT/CN2021/097369 2021-05-31 2021-05-31 Drug repurposing to treat primary lung adenocarcinoma based on deep embeddings of single-cell sequencing analysis WO2022252044A1 (en)

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