METHODS OF TREATING WHSC1-OVEREXPRESSING CANCERS BY INHIBITING SETD2
The present disclosure provides methods and pharmaceutical compositions for treating or slowing the progression of cancers that overexpress the histone methyltransferase WHSC1, e.g., t(4; 14) multiple myeloma, by administering to a subject in need thereof a therapeutically effective amount of an inhibitor of the histone methyltransferase, SETD2.
1 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a SETD2 inhibitor, wherein the cancer overexpresses WHSC1.
2 . The method of claim 1 , wherein overexpression of WHSC1 by said cancer is determined prior to administering said SETD2 inhibitor.
3 . The method of claims 1 - 2 , wherein the SETD2 inhibitor is a Substituted Indole Compound.
4 . The method of claim 3 , wherein the SETD2 inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.
5 . The method of claims 1 - 2 , wherein the SETD2 inhibitor is not a Substituted Indole Compound.
6 . The method of claims 1 - 5 , wherein the cancer that overexpresses WHSC1 is a hematologic cancer.
7 . The method of claim 6 , wherein the hematologic cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma (MM), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, splenic marginal zone lymphoma, follicular lymphoma (FL), Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), hairy cell leukemia (HCL), Burkitt's lymphoma (BL), Richter's transformation, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myelogenous leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, MALT lymphoma, precursor T-lymphoblastic lymphoma, T-cell lymphoma, mast cell leukemia, adult T cell leukemia/lymphoma, aggressive NK-cell leukemia, and angioimmunoblastic T-cell lymphoma.
8 . The method of claim 7 , wherein the hematologic cancer is multiple myeloma.
9 . The method of claim 8 , wherein the multiple myeloma contains a chromosomal translocation or a chromosomal deletion.
10 . The method of claim 9 , wherein the multiple myeloma contains a chromosomal translocation.
11 . The method of claim 10 , wherein the chromosomal translocation involves chromosome 14.
12 . The method of claim 11 , wherein the chromosomal translocation is a t (4;14) translocation.
13 . The method of claim 12 , wherein the chromosomal translocation is a non-t(4;14) translocation.
14 . The method of claim 13 , wherein the non-t(4;14) translocation is selected from the group consisting of a t(14; 16); t(11; 14); t(14;20), t(8; 14), and t(6; 14) translocation.
15 . The method of claim 9 , wherein the multiple myeloma contains a chromosomal deletion.
16 . The method of claim 15 , wherein the deletion is selected from the group consisting of del(17p) and del(13).
17 . The method of any one of claims 1 - 5 , wherein the cancer that overexpresses WHSC1 is a solid tumor.
18 . The method of claim 17 , wherein the solid tumor is selected from the group consisting of esophageal cancer, kidney cancer, stomach cancer, hepatocellular carcinoma, glioblastoma, central nervous system (CNS) cancer, soft tissue cancer, lung cancer, breast cancer, bladder/urinary tract cancer, head and neck cancer, melanoma, prostate cancer, testicular cancer, pancreatic cancer, skin cancer, endometrial cancer, ovarian cancer, colon cancer, and colorectal cancer.
19 . The method of any one of claims 1 - 18 , wherein the subject is a mammal.
20 . The method of any one of claims 1 - 18 , wherein the subject is a human.
21 . The method of any one of claims 1 - 20 , wherein the compound is formulated for systemic or local administration.
22 . The method of any one of claims 1 - 20 , wherein the compound is formulated for oral, nasal, intra-peritoneal, or intra-tumoral administration.
23 . The method of any one of claims 1 - 20 , wherein the compound is formulated for intravenous administration, intramuscular administration, or subcutaneous administration.
24 . A method of inhibiting the trimethylation of lysine 36 on histone H3 (H3K36me3) in a cell, the method comprising contacting said cell with a SETD2 inhibitor, wherein the cell overexpresses WHSC1.
25 . The method of claim 24 , wherein the SETD2 inhibitor is a Substituted Indole Compound.
26 . The method of claim 25 , wherein the SETD2 inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.
27 . The method of claim 24 , wherein the SETD2 inhibitor is not a Substituted Indole Compound.
28 . The method of any one of claims 24 - 27 , wherein inhibiting trimethylation of lysine 36 on histone H3 in a cell occurs in vitro.
29 . The method of any one of claims 24 - 27 , wherein inhibiting trimethylation of lysine 36 on histone H3 in a cell occurs in vivo.
30 . The method of any one of claims 24 - 29 , wherein the cell is derived from a hematologic cancer.
31 . The method of claim 30 , wherein the hematologic cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma (MM), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, splenic marginal zone lymphoma, follicular lymphoma (FL), Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), hairy cell leukemia (HCL), Burkitt's lymphoma (BL), Richter's transformation, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myelogenous leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, MALT lymphoma, precursor T-lymphoblastic lymphoma, T-cell lymphoma, mast cell leukemia, adult T cell leukemia/lymphoma, aggressive NK-cell leukemia, and angioimmunoblastic T-cell lymphoma.
32 . The method of claim 31 , wherein the hematologic cancer is multiple myeloma.
33 . The method of claim 32 , wherein the multiple myeloma contains a chromosomal translocation or a chromosomal deletion.
34 . The method of claim 33 , wherein the multiple myeloma contains a chromosomal translocation.
35 . The method of claim 34 , wherein the chromosomal translocation involves chromosome 14.
36 . The method of claim 34 , wherein the chromosomal translocation is a t(4; 14) translocation.
37 . The method of claim 34 , wherein the chromosomal translocation is a non-t(4;14) translocation.
38 . The method of claim 37 , wherein the non-t(4; 14) translocation is selected from the group consisting of a t(14; 16); t(11; 14); t(14;20), t(8; 14), and t(6; 14) translocation.
39 . The method of claim 33 , wherein the multiple myeloma contains a deletion.
40 . The method of claim 39 , wherein the deletion is selected from the group consisting of del(17p) and del(13).
41 . The method of claim 24 , wherein the cell is derived from a solid tumor.
42 . The method of claim 41 , wherein the solid tumor is selected from the group consisting of esophageal cancer, kidney cancer, stomach cancer, hepatocellular carcinoma, glioblastoma, central nervous system (CNS) cancer, soft tissue cancer, lung cancer, breast cancer, bladder/urinary tract cancer, head and neck cancer, melanoma, prostate cancer, testicular cancer, pancreatic cancer, skin cancer, endometrial cancer, ovarian cancer, colon cancer, and colorectal cancer.
43 . The method of any one of claims 29 - 42 , wherein the in vivo cell is in a mammal.
44 . The method of any one of claims 29 - 42 , wherein the in vivo cell is in a human.