TREATING DISORDERS ASSOCIATED WITH ABERRANT ADRENOCORTICAL CELL BEHAVIOR
Methods and agents are provided for treatment of disorders associated with aberrant adrenocortical cell behavior, including (but not limited to) treatment of adrenocortical carcinoma (ACC) and/or Cushing's syndrome. Such methods involve administration of an agent which exhibits an IC 50 value against huACAT1 of less than 10 μM, and one or more further characteristics including effects on adrenocortical cells, disruption of cholesterol homeostasis, reduction in steroid biosynthesis, reduction of mitochondrial function, and/or preferential binding to by low-density lipoprotein (LDL).
1 . A method for treating a disorder associated with aberrant adrenocortical cell behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent which: (a) exhibits an IC 50 value against huACAT1 of less than 10 μM; and (b) has one or more effects on adrenocortical cells, and wherein the agent is not N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea or a salt thereof.
2 . The method of claim 1 , wherein effects on adrenocortical cells are assessed by measuring a reduction of cholesterol esters.
3 . The method of claim 1 , wherein effects on adrenocortical cells are assessed by measuring apoptosis.
4 . The method of claim 1 , wherein effects on adrenocortical cells are assessed by measuring a marker of apoptosis.
5 . The method of claim 4 , wherein the marker of apoptosis is Caspase 3, Caspase 7 or both Caspase 3 and Caspase 7 activity.
6 . The method of claim 4 , wherein the marker of apoptosis is activation of the unfolded protein response (UPR).
7 . The method of claim 6 , wherein activation of the UPR is determined by measuring expression of an activated XBP-1 splice variant.
8 . The method of claim 1 , wherein effects on adrenocortical cells are assessed by measuring a reduction of steroid biosynthesis.
9 . The method of claim 8 , wherein the steroid is cortisol.
10 . The method of claim 1 , wherein effects on adrenocortical cells are assessed by measuring cholesterol homeostasis.
11 . A method for treating a disorder associated with aberrant adrenocortical cell behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent which: (a) exhibits an IC 50 value against human ACAT1 (huACAT1) of less than 10 μM; and (b) disrupts cholesterol homeostasis in adrenocortical cells; wherein the agent is not N-(2,6-bis(1-methylethyl)-phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea or a salt thereof.
12 . A method for treating a disorder associated with aberrant adrenocortical cell behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent which: (a) exhibits an IC 50 value against huACAT1 of less than 10 μM; and (b) reduces steroid biosynthesis in adrenocortical cells, and wherein the agent is not N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)-methyl)urea or a salt thereof.
13 . A method for treating a disorder associated with aberrant adrenocortical cell behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent which: (a) exhibits an IC 50 value against huACAT1 of less than 10 μM; and (b) reduces mitochondrial function in adrenocortical cells, and wherein the agent is not N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)-methyl)urea or a salt thereof.
14 . A method for treating a disorder associated with aberrant adrenocortical cell behavior in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent which: (a) exhibits an IC 50 value against huACAT1 of less than 10 μM; and (b) is preferentially bound by low-density lipoprotein (LDL), and wherein the agent is not N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)-methyl)urea or a salt thereof.
15 . The method of claim 1 , wherein the agent exhibits an IC 50 value against huACAT1 of less than 5 μM.
16 . The method of claim 15 , wherein the agent exhibits an IC 50 value against huACAT1 of less than 3 μM, 1 μM, 0.5 μM, 0.3 μM, 0.1 μM, 0.05 μM, 0.03 μM, 0.01 μM, 0.005 μM, 0.003 μM, or 0.001 μM.
17 . The method of claim 1 , wherein the agent is Compound No. 3 or Compound No. 5.
18 . The method of claim 1 , wherein the disorder is adrenocortical carcinoma, benign adenoma, increased hormone production, metastatic adrenocortical carcinoma, congenital adrenal hyperplasia, Cushing's syndrome, excess cortisol production, symptoms associated with excess cortisol production, hyperaldosteronism, 21-hydroxylase deficiency, reduces adrenocortical tumor size, or aberrant adrenal hormone production.
19 . The method of claim 1 , wherein the disorder is adrenocortical carcinoma.
20 . The method of claim 1 , wherein the disorder is Cushing's syndrome.