Method for treating cancer
View Patent ↗The present invention provides a method for treating or alleviating a symptom of a disorder, e.g., immune evasion, cancer-cell induced immune dysfunction, reduced immune response, lowered inflammation, decreased expression of a major histocompatibility complex (MHC), or cancer, characterized by aberrant, misregulated, or increased Enhancer of Zeste Homolog 2 (EZH2) activity in a cell or subject in need thereof by contacting the cell or administering to the subject a therapeutically effective amount of an EZH2 inhibitor.
1. A method of inhibiting the ability of a cancer cell to induce immune dysfunction, comprising a step of contacting the cell with a therapeutically effective amount of an EZH2 inhibitor, wherein the cell (1) comprises aberrant, misregulated, or increased EZH2 activity; or (2) comprises a chromosomal translocation t(x; 18)(p11.2;q11.2) that causes a SS18-SSX fusion gene; or (3) has reduced function and/or expression of INI1.
2. The method of claim 1 , wherein the cell comprises aberrant, misregulated, or increased EZH2 activity.
3. The method of claim 1 , wherein the cell comprises a chromosomal translocation t(x; 18)(p11.2;q11.2), wherein the translocation causes a SS18-SSX fusion gene.
4. The method of claim 1 , wherein the cell has reduced function or expression of INI1.
5. The method of claim 4 , wherein the cell has reduced function and expression of INI1.
6. The method of claim 1 , wherein the EZH2 inhibitor is Compound A, having the following formula:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the EZH2 inhibitor is selected from the group consisting of
and pharmaceutically acceptable salts thereof.
8. The method of claim 1 , wherein the cancer cell is in a subject.
9. The method of claim 8 , wherein the subject is human.
10. The method of claim 1 , wherein the ability of the cancer cell to induce immune dysfunction is characterized by reduced expression of one or more of MHC, β2 microglobulin, Tumor Necrosis Factor (TNF) receptor, Low Molecular Mass Polypeptide 2 (LMP2), Low Molecular Mass Polypeptide 7 (LMP7), Transporter Associated with Antigen Processing (TAP), and TAP-associated glycoprotein (tapasin) in the cancer cell when compared to a non-cancerous cell.
11. The method of claim 10 , wherein the MHC is human leukocyte antigen (HLA), wherein the HLA is selected from the group consisting of HLA-A, HLA-B, HLA-C, HLDA-DM alpha, HLA-DM beta, HLA-DO alpha, HLA-DO beta 1, HLA-DP alpha 1, HLA-DP beta 1, HLA-DR alpha, HLA-DR beta 1, HLA-DR beta 3, HLA-DR beta 4, HLA-E, HLA-F, HLA-G, HLA-K, and HLA-L.
12. A method of treating or alleviating symptoms of a disorder characterized by cancer-cell induced immune dysfunction in a subject comprising a step of administering to the subject a therapeutically effective amount of an EZH2 inhibitor; wherein the subject (1) comprises a chromosomal translocation t(x; 18) that causes a SS18-SSX fusion gene; or (2) has reduced function and/or expression of INTL.
13. The method of claim 12 , wherein the subject comprises aberrant, misregulated, or increased EZH2 activity.
14. The method of claim 12 , wherein the subject comprises a chromosomal translocation t(x; 18)(p11.2;q11.2), wherein the translocation causes a SS18-SSX fusion gene.
15. The method of claim 12 , wherein the subject has reduced function or expression of INI1.
16. The method of claim 15 , wherein the subject has reduced function and expression of INI1.
17. The method of claim 12 , wherein the EZH2 inhibitor is Compound A, having the following formula:
or a pharmaceutically acceptable salts thereof.
18. The method of claim 12 , wherein the EZH2 inhibitor is selected from the group consisting of
and pharmaceutically acceptable salts thereof.
19. The method of claim 12 , wherein the method further comprises administering a chemotherapeutic compound.
20. The method of claim 19 , wherein the chemotherapeutic compound is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor.