COMBINATION THERAPIES COMPRISING MYC MODULATION
The present disclosure relates to combination therapies. The combination therapy may comprise administration of an expression repressor and a kinase inhibitor. In some embodiments, the expression repressor comprises a targeting moiety that binds a MYC promoter, anchor sequence, or super-enhancer. In some embodiments, the expression repressor comprises an effector moiety that represses transcription or methylates DNA. The compositions and methods can be used, for example, to treat cancers such as HCC.
1 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a targeting moiety that binds to a MYC promoter, and
(b) optionally, an effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC; and
(2) a compound having the general structure of Formula (I):
wherein:
R 1 is alkyl, cycloalkyl, or aryl;
R 2 is halo, alkyl, or H;
R 3 , R 4 , R 5 , R 6 , R 7 , are each independently H or alkyl;
R 8 and R 9 together form an optionally substituted aromatic ring;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
2 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a first targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
(b) optionally, a first effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC; and
(2) a compound having the general structure of Formula (I):
wherein:
R 1 is alkyl, cycloalkyl, or aryl;
R 2 is halo, alkyl, or H;
R 3 , R 4 , R 5 , R 6 , R 7 , are each independently H or alkyl;
R 8 and R 9 together form an optionally substituted aromatic ring;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
3 . The method of claim 1 or 2 , wherein R 1 is alkyl or cycloalkyl.
4 . The method of any of the preceding claims , wherein R 1 =cyclopropane.
5 . The method of any of the preceding claims , wherein R 2 is halo.
6 . The method of any of the preceding claims , wherein R 2 =Cl.
7 . The method of any of the preceding claims , wherein R 3 , R 4 , R 5 , R 6 , R 7 , are each H.
8 . The method of any of the preceding claims , wherein the substituted aromatic ring is a substituted phenyl ring.
9 . The method of any of the preceding claims , wherein the compound of Formula (I) comprises:
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
10 . The method of any of the preceding claims , wherein the compound of Formula (I) is administered orally.
11 . The method of any of the preceding claims , wherein the compound of Formula (I) is administered at a dose of 6-10 (e.g., about 8) or 10-14 (e.g., about 12) mg per day.
12 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a targeting moiety that binds to a MYC promoter, and
(b) optionally, an effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC; and
(2) a compound having the general structure of Formula (II):
wherein R 1 is:
wherein X=C or N, given that one or two Xs are Ns; and R 12 is an electron pair, H or methyl;
(2) halogen; or
(3) methyl halogen;
R 2 is H or methyl;
R 3 is H or methyl;
R 4 is H or methyl;
R 5 is —OH or —O-methyl;
R 6 is H or methyl;
R 7 is H or methyl;
R 8 is —(CH 2 ) n —N(R 13 ) 2 , wherein n=2-6, and R 13 =H or methyl;
R 9 is H or methyl;
R 10 is —(CO)—R 14 , wherein R 14 is alkyl or alkene; and
R 11 is H or methyl;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
13 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
(1) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a first targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
(b) optionally, a first effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC; and
(2) a compound having the general structure of Formula (II):
wherein R 1 is:
wherein X=C or N, given that one or two Xs are Ns; and R 12 is an electron pair, H or methyl;
(2) halogen; or
(3) methyl halogen;
R 2 is H or methyl;
R 3 is H or methyl;
R 4 is H or methyl;
R 5 is —OH or —O-methyl;
R 6 is H or methyl;
R 7 is H or methyl;
R 8 is —(CH 2 ) n —N(R 13 ) 2 , wherein n=2-6, and R 13 =H or methyl;
R 9 is H or methyl;
R 10 is —(CO)—R 14 , wherein R 14 is alkyl or alkene; and
R 11 is H or methyl;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
14 . The method of claim 12 or 13 , wherein R 1 is:
wherein X=C or N, given that one or two Xs are N; and R 15 is an electron pair, H or methyl.
15 . The method of any of claims 12-14 , wherein R 1 is:
16 . The method of any of claims 12-15 , wherein R 1 is:
17 . The method of any of claims 12-16 , wherein:
R 2 is H;
R 3 is H;
R 4 is H;
R 5 is —O-methyl;
R 6 is H;
R 7 is methyl;
R 8 is —(CH 2 ) 2 —N(methyl) 2 , wherein n=2-6, and R 13 =H or methyl;
R 9 is H;
R 1 is —(CO)-ethylene; and
R 11 is H.
18 . The method of any of claims 12-17 , wherein Formula (II) is:
19 . The method of any of claims 12-18 , wherein the compound of Formula (II) is administered orally.
20 . The method of any of claims 12-19 , wherein the compound of Formula (II) is administered at a dose of 40-100 (e.g., about 80) mg per day.
21 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
(I) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a targeting moiety that binds to a MYC promoter, and
(b) optionally, an effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC; and
(II) an ERK inhibitor (e.g., ulixertinib), an AKT inhibitor (e.g., MK-2206), or a MEK inhibitor (e.g., trametinib).
22 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
(I) a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a first targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
(b) optionally, a first effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC; and
(II) an ERK inhibitor (e.g., ulixertinib), an AKT inhibitor (e.g., MK-2206), or a MEK inhibitor (e.g., trametinib).
23 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a targeting moiety that binds to a MYC promoter, and
(b) optionally, an effector moiety,
wherein the expression repressor is capable of decreasing expression of MYC;
wherein the cancer is resistant to osimertinib.
24 . A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject:
a nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor, wherein the expression repressor comprises:
(a) a first targeting moiety that binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of any of SEQ ID NOs: 83, 2, 3, 75-86, 97-107, 109, 110, 190-192, or 199-202, and
(b) optionally, a first effector moiety,
wherein the cancer is resistant to osimertinib.
25 . The method of any of the preceding claims wherein the cancer is a lung cancer, e.g., NSCLC.
26 . The method of any of the preceding claims , wherein the cancer is a hepatocellular carcinoma (HCC), Fibrolamellar Hepatocellular Carcinoma (FHCC), Cholangiocarcinoma, Angiosarcoma, or secondary liver cancer.
27 . The method of any of claims 1-26 , wherein the nucleic acid comprises an RNA, e.g., an mRNA.
28 . The method of any of claims 2-27 , wherein:
the first targeting moiety binds a genomic locus comprising at least 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 83, and
the expression repressor comprises the first effector moiety, wherein the first effector moiety comprises a DNA methyltransferase.
29 . The method of claim 28 , wherein the first targeting moiety comprises a zinc finger domain.
30 . The method of claim 28 or 29 , wherein the first targeting moiety comprises an amino acid sequence according to SEQ ID NO: 13 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
31 . The method of any of claims 28-30 , wherein the first effector moiety comprises MQ1 or a functional variant or fragment thereof.
32 . The method of any of claims 28-31 , wherein the first effector moiety comprises a sequence of SEQ ID NO: 19 or 87, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
33 . The method of any of claims 28-32 , wherein the first effector moiety comprises a sequence of SEQ ID NO: 129, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
34 . The method of any of claim 28 , wherein the RNA comprises a nucleotide sequence encoding the first targeting moiety, wherein the nucleotide sequence encoding the first targeting moiety comprises a sequence according to SEQ ID NO: 131 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
35 . The method of any of claims 28-34 , wherein the RNA comprises a nucleotide sequence encoding the first effector moiety, wherein the nucleotide sequence encoding the first effector moiety comprises a sequence according to SEQ ID NO: 132, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
36 . The method of any of claims 28-35 , wherein the RNA comprises a nucleotide sequence according to SEQ ID NO: 130, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
37 . The method of any of claims 28-36 , wherein the RNA further encodes a second expression repressor, wherein the second expression repressor comprises:
a second targeting moiety that binds a second genomic locus, and
a second effector moiety.
38 . The method of claim 37 , wherein the second targeting moiety binds a second genomic locus comprising at least 14, 15, 16, 17, 18, 19, or 20 nucleotides of the sequence of SEQ ID NO: 77.
39 . The method of claim 37 or 38 , wherein the second targeting moiety comprises a zinc finger domain.
40 . The method of any of claims 37-39 , wherein the second targeting moiety comprises an amino acid sequence according to SEQ ID NO: 7, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
41 . The method of any of claims 37-40 , wherein the second effector moiety comprises KRAB or a functional variant or fragment thereof.
42 . The method of any of claims 37-41 , wherein the second effector moiety comprises an amino acid sequence according to SEQ ID NO: 18, or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
43 . The method of any of claims 37-42 , wherein the second expression repressor comprises an amino acid sequence according to SEQ ID NO: 24 or a sequence with at least 80, 85, 90, 95, 99, or 100% identity thereto, or having no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 positions of difference thereto.
44 . The method of any of claims 37-43 , wherein the RNA comprises a nucleotide sequence according to SEQ ID NOs: 113, 196, or 208.
45 . The method of any of the preceding claims , wherein the nucleic acid is formulated in lipid nanoparticles (LNPs), wherein optionally the nucleic acid is encapsulated inside of the LNPs.
46 . The method of any of the preceding claims , wherein the nucleic acid (e.g., RNA, e.g., mRNA) encoding the expression repressor is administered as an IV infusion, e.g., over 80-120 minutes, e.g., every 2 weeks.
47 . The method of any of the preceding claims , wherein the nucleic acid is administered at a dose of about 0.001 mg/kg to 1.5 mg/kg or about 0.002 mg/kg to 1.5 mg/kg, e.g., administered every 1, 2, 3, 4, 5, 6 or 7 weeks.
48 . The method of any of the preceding claims , wherein the nucleic acid (e.g., RNA, e.g., mRNA) encoding the expression repressor and the compound having the general structure of Formula (I) or Formula (II) are administered on different days.
49 . The method of any of the preceding claims , wherein the nucleic acid (e.g., RNA, e.g., mRNA) encoding the expression repressor and the compound having the general structure of Formula (I) or Formula (II) are administered on the same day.
50 . The method of claim 49 , wherein the of the nucleic acid (e.g., RNA, e.g., mRNA) encoding the expression repressor is administered prior to administration of the compound having the general structure of Formula (I) or Formula (II).
51 . The method of claim 49 or 50 , wherein the compound having the general structure of Formula (I) or Formula (II) is administered between 1-24 hours after completion of administration of the nucleic acid (e.g., RNA, e.g., mRNA) encoding an expression repressor.