Treatment of adrenocortical carcinoma with selective glucocorticoid receptor modulators (SGRMs) and antibody checkpoint inhibitors
Methods and compositions for treating a subject suffering from adrenocortical carcinoma and having excess cortisol are disclosed. The methods provide therapeutic benefits including reduction of ACC tumor load, restoration of T-cell and natural killer (NK) cell signaling pathways, increase in T-cell and NK cell infiltration into the ACC tumor, reduction of neutrophil infiltration into the ACC tumor in the patient, and other therapeutic benefits. The methods include administration of a glucocorticoid receptor modulator (GRM) (which may be a selective glucocorticoid receptor modulator (SGRM)) and an antibody checkpoint inhibitor. In embodiments, the GRM (e.g., a SGRM) is orally administered. The GRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.
1 . A method of treating a patient suffering from adrenocortical carcinoma (ACC), said patient having an ACC tumor or tumors, the amount of said ACC tumor or tumors being the ACC tumor load of the patient, the patient having cortisol excess, and having lower expression of the gene ZNF683 in said ACC tumor or tumors as compared to ZNF683 expression in ACC tumors in patients who suffer from ACC without cortisol excess, the method comprising:
Identifying a patient
a) suffering from adrenocortical carcinoma (ACC),
b) suffering from cortisol excess, and
c) having lower expression of the gene ZNF683 as compared to ZNF683 expression in patients without cortisol excess who suffer from ACC;
administering to said patient a combination treatment comprising administration of
1) a selective glucocorticoid receptor modulator (SGRM),
wherein said SGRM is a heteroaryl-ketone fused azadecalin compound having the formula:
wherein
R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1 to 4 R 1a groups each independently selected from R 1a ;
each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, N-oxide, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;
ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R 2c groups;
alternatively, two R 2 groups linked to the same carbon are combined to form an oxo group (═O);
alternatively, two R 2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2d groups;
R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each R 2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, and NR 2a R 2b ;
each R 2d is independently selected from the group consisting of hydrogen and C 1-6 alkyl, or two R 2d groups attached to the same ring atom are combined to form (═O);
R 3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R 3a groups;
each R 3a is independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and
subscript n is an integer from 0 to 3;
or salts and isomers thereof,
and
2) An antibody checkpoint inhibitor
to said identified patient;
thereby achieving a better treatment outcome from said identified patient than would be achieved by treatment with an antibody checkpoint inhibitor alone, wherein said treatment outcome is selected from a) reduction in said patient's ACC tumor load, b) restoration of T-cell and natural killer (NK) cell signaling pathways in the patient, c) increased T-cell and NK cell infiltration into the ACC in the patient, and d) reduced neutrophil infiltration into the ACC in the patient.
2 . The method of claim 1 , wherein the antibody checkpoint inhibitor is selected from an antibody effective against PD-1, an antibody effective against CTLA-4, an antibody effective against PD-L1, and an antibody effective against PD-L2.
3 . The method of claim 1 , wherein the method further comprises administering a taxane chemotherapeutic agent.
4 . The method of claim 3 , wherein said taxane chemotherapeutic agent is nab-paclitaxel.
5 . The method of claim 1 , wherein said SGRM is the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl) sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl) (4-(trifluoromethyl) pyridin-2-yl) methanone, termed relacorilant, which has the following structure:
6 . The method of claim 1 , wherein the antibody checkpoint inhibitor is selected from an antibody effective against PD-1, an antibody effective against CTLA-4, and an antibody effective against PD-L1.
7 . The method of claim 1 , wherein the SGRM is the heteroaryl-ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4, 4a, 5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl) methanone (termed “CORT113176”), which has the following structure: