Granted Patent B2

US 12,667,546 · App. 17/293,362 · Granted Jun 30, 2026

Inventors: Wai Leong Tam (Singapore, SG); Ser Yue Loo (Singapore, SG); Li Ping Toh (Singapore, SG)

Assignee: AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH

A61K31/07A61K31/513A61K45/06A61P35/00A61P35/04

Abstract

Claims (41)

1 . A method of inducing mesenchymal-epithelial transition (MET) in a cancer cell, the method comprising contacting the cell with an inducer of mesenchymal-epithelial transition for a time and under conditions sufficient to induce MET in the cell,

wherein the cancer cell is a basal-like (mesenchymal-like) cancer cell,

wherein the inducer of MET is an adenosine/adrenergic receptor modulator, a GABA receptor modulator, a NMDA receptor modulator, or a neurotransmitter;

wherein the adenosine/adrenergic receptor modulator is idazoxan hydrochloride, (±)-atenolol, or 1,3-Dipropyl-8-p-sulfophenylxanthine;

wherein the GABA receptor modulator is (±)-nipecotic acid or chlormethiazole hydrochloride;

wherein the NMDA receptor modulator is 1-aminocyclopropanecarboxylic acid hydrochloride or (±)-2-amino-4-phosphonobutyric acid;

wherein the neurotransmitter is ABT-418 hydrochloride, Apomorphine hydrochloride hemihydrate, Varenicline Tartrate, or ML 10302; and

wherein the cancer cell is a cancer cell from triple negative breast cancer, head and neck cancer, lung cancer, pancreatic cancer, ovarian cancer, gastric cancer or colorectal cancer.

2 . The method of claim 1 , wherein the cancer cell is triple negative breast cancer.

3 . The method of claim 1 , wherein the cancer cell is a cancer cell that is resistant to standard-of-care therapies.

4 . The method of claim 1 , wherein the method further comprises contacting the cell with:

i) a chemotherapeutic agent selected from chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, 5-fluorouracil, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, or endostatin,

ii) an epigenetic-modifying compound selected from vorinostat (SAHA), belinostat (PXD101), LAQ824, Panobinostat (LBH589), entinostat (MS-275), tacedinaline (CI994) or mocetinostat (MGCD0103), or

iii) an immune checkpoint inhibitor selected from an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, ID01,_1D02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collageneous structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA or VTCN1, following induction of MET in the cancer cell.

5 . The method of claim 1 , wherein the method further comprises contacting the basal-like (or mesenchymal-like) cancer cell with an inhibitor of lipid metabolism, wherein the inhibitor of lipid metabolism is selected from etomoxir, perhexiline, oxfenicine, 4-bromocrotonic acid, tracsin C, thiazolidinediones, trimetazidine, ranolazine or JZL184.

6 . The method of claim 5 , wherein the inhibitor of lipid metabolism is etomoxir, perhexiline or oxfenicine.

7 . The method of claim 1 , wherein the method comprises inhibiting the progress of growth of a basal-like (mesenchymal-like) cancer in a patient or sensitizing a patient to an anti-cancer therapy.

8 . A method of inhibiting the progress of growth of a basal-like (mesenchymal-like) cancer in a patient in need thereof, the method comprising administering an inducer of mesenchymal-epithelial transition (MET) in combination with a chemotherapeutic agent, an epigenetic-modifying compound, an immunomodulatory agent, or an inhibitor of lipid metabolism to the patient, for a time and under conditions to inhibit the progress of growth of cancer in the patient,

wherein the inducer of MET is an adenosine/adrenergic receptor modulator, a GABA receptor modulator, a NMDA receptor modulator, or a neurotransmitter;

wherein the adenosine/adrenergic receptor modulator is idazoxan hydrochloride, (±)-atenolol, or 1,3-Dipropyl-8-p-sulfophenylxanthine;

wherein the GABA receptor modulator is (±)-nipecotic acid or chlormethiazole hydrochloride;

wherein the NMDA receptor modulator is 1-aminocyclopropanecarboxylic acid hydrochloride or (±)-2-amino-4-phosphonobutyric acid;

wherein the neurotransmitter is ABT-418 hydrochloride, Apomorphine hydrochloride hemihydrate, Varenicline Tartrate, or ML 10302;

wherein the chemotherapeutic agent is selected from chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, 5-fluorouracil, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin or endostatin,

wherein the epigenetic-modifying compound is selected from vorinostat (SAHA), belinostat (PXD101), LAQ824, Panobinostat (LBH589), entinostat (MS-275), tacedinaline (CI994) or mocetinostat (MGCD0103),

wherein the immune checkpoint inhibitor is selected from an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, ID01,_1D02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collageneous structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA or VTCN1,

wherein the inhibitor of lipid metabolism is selected from etomoxir, perhexiline, oxfenicine, 4-bromocrotonic acid, tracsin C, thiazolidinediones, trimetazidine, ranolazine or JZL184, and

wherein the cancer is triple negative breast cancer, head and neck cancer, lung cancer, pancreatic cancer, ovarian cancer, gastric cancer or colorectal cancer.

9 . A method of identifying and inhibiting the progress of growth of a cancer in a cancer patient responsive to a combination therapy comprising a mesenchymal-epithelial transition (MET) inducing compound in combination with a chemotherapeutic agent, an epigenetic-modifying compound, an immunomodulatory agent, or an inhibitor of lipid metabolism, the method comprising:

a) detecting a mesenchymal subtype of cancer in a sample obtained from the patient, wherein the presence of a mesenchymal subtype of cancer indicates that the patient is responsive to the combination therapy; and

b) administering the combination therapy to the patient;

wherein the MET inducing compound is an adenosine/adrenergic receptor modulator, a GABA receptor modulator, a NMDA receptor modulator, or a neurotransmitter;

wherein the adenosine/adrenergic receptor modulator is idazoxan hydrochloride, (±)-atenolol, or 1,3-Dipropyl-8-p-sulfophenylxanthine;

wherein the GABA receptor modulator is (±)-nipecotic acid or chlormethiazole hydrochloride;

wherein the NMDA receptor modulator is 1-aminocyclopropanecarboxylic acid hydrochloride or (±)-2-amino-4-phosphonobutyric acid;

wherein the neurotransmitter is ABT-418 hydrochloride, Apomorphine hydrochloride hemihydrate, Varenicline Tartrate, or ML 10302;

wherein the chemotherapeutic agent is selected from chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, 5-fluorouracil, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, or endostatin,

wherein the epigenetic-modifying compound is selected from vorinostat (SAHA), belinostat (PXD101), LAQ824, Panobinostat (LBH589), entinostat (MS-275), tacedinaline (CI994), and mocetinostat (MGCD0103),

wherein the immune checkpoint inhibitor selected from an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, ID01,_1D02, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collageneous structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, or VTCN1,

wherein the inhibitor of lipid metabolism is selected from etomoxir, perhexiline, oxfenicine, 4-bromocrotonic acid, tracsin C, thiazolidinediones, trimetazidine, ranolazine or JZL184, and

wherein the cancer is triple negative breast cancer, head and neck cancer, lung cancer, pancreatic cancer, ovarian cancer, gastric cancer or colorectal cancer.

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (51)