Methods for manipulating cell state transitions in cancer

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.

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.