Use of ape1/ref-1 inhibitors in combination therapies for treatment of cancer
OwnerMark R. Kelley, Melissa L. Fishelinventors
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Abstract
Combination therapies including a Apurinic/Apyrimidinic Endonuclease/reduction-oxidation (redox) Factor-1 (APE1/Ref-1) inhibitor specific to inhibit the redox function of APE1/Ref-1 are disclosed herein. The Combination therapies can be used for treating various cancers, as well as other angiogenesis-mediated diseases (e.g., retinal diseases, cardiovascular diseases).
Claims28
A combination therapy comprising an Apurinic/Apyrimidinic Endonuclease/reduction-oxidation (redox) Factor-1 (APE1/Ref-1) inhibitor, wherein the APE1/Ref-1 inhibitor inhibits the redox function of APE1/Ref-1 and a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of a Bcl-2 inhibitor, a PTEN inhibitor, a WNT/β-catenin inhibitor, a pyruvate dehydrogenase (PDH) inhibitor, a α-ketoglutarate dehydrogenase inhibitor, a Notch3 inhibitor, a photodynamic therapy (PDT), and combinations thereof.
A combination therapy comprising (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014), wherein the APE1/Ref-1 inhibitor inhibits the redox function of APE1/Ref-1, and a second therapeutic agent.
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The method as set forth in claim 24, wherein the cancer is selected from the group consisting of prostate, pancreatic, pancreatic ductal adenocarcinoma, cervical, ovarian, osteosarcoma, germ cell tumor, colon/colorectal, bladder, head and neck, gastric/gastro-esophageal, neuroectodermal tumors, rhabdomyosarcomas, pancreaticobiliary, adult gliomas, non-small cell lung, hepatocellular, multiple myeloma, esophageal, breast, pediatric ependymoma, and melanoma.
The method as set forth in claim 24, wherein the cancer is colon cancer, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being selected from the group consisting of doxorubicin, 5-fluorouracil (5-FU), CPI-613, oxaliplatin, napabucasin, CP-839, and combinations thereof.
The method as set forth in claim 24, wherein the cancer is leukemia, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being retinoic acid.
The method as set forth in claim 24, wherein the cancer is malignant peripheral nerve sheath tumors, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being a survivin inhibitor.
The method as set forth in claim 24, wherein the cancer is non-small cell lung carcinoma, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being selected from the group consisting of a Bcl-2 inhibitor, a photodynamic therapy, and combinations thereof.
The method as set forth in claim 24, wherein the cancer is prostate cancer, and the combination therapy comprises an APE1/Ref-1 inhibitor being selected from the group consisting of 5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), and combinations thereof, and a second therapeutic agent being a survivin inhibitor.
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The method as set forth in claim 25, wherein the retinal disease is selected from the group consisting of choroidal neovascularization (CNV), age-related macular degeneration (AMD), retinopathy of prematurity (ROP), diabetic retinopathy (DR)), and ischemic retinopathy.
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Dependencies are inferred from the claim text.