Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease

• Published in: The journal of clinical endocrinology and metabolism Vol. 106; no. 1; pp. e232 - e246
• Main Authors: Zhang, Dongyun, Damoiseaux, Robert, Babayan, Lilit, Rivera-Meza, Everett Kanediel, Yang, Yingying, Bergsneider, Marvin, Wang, Marilene B, Yong, William H, Kelly, Kathleen, Heaney, Anthony P
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-01-2021; Copyright Oxford University Press
• Subjects: 1-Phosphatidylinositol 3-kinase; ACTH; ACTH-Secreting Pituitary Adenoma - drug therapy; ACTH-Secreting Pituitary Adenoma - genetics; ACTH-Secreting Pituitary Adenoma - metabolism; ACTH-Secreting Pituitary Adenoma - pathology; Adenoma - drug therapy; Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - analysis; Adrenocorticotropic Hormone - metabolism; Analysis; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Care and treatment; Cell proliferation; Cell Proliferation - drug effects; Cell viability; Clinical s; Clinical trials; Corticosterone; Corticotrophs - drug effects; Corticotrophs - metabolism; Corticotrophs - pathology; Cushing syndrome; Cushing's disease; Drug development; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; High-Throughput Screening Assays; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Immunological tolerance; Intermedin; Medical colleges; Mice; Mice, Nude; Molecular Targeted Therapy - methods; Morpholines - pharmacology; Morpholines - therapeutic use; Nervous system diseases; Oral administration; Patients; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; Pituitary; Pituitary ACTH Hypersecretion - drug therapy; Pituitary ACTH Hypersecretion - genetics; Pituitary ACTH Hypersecretion - metabolism; Pituitary ACTH Hypersecretion - pathology; Proopiomelanocortin; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Secretion; Tumor Cells, Cultured; Tumors; Vorinostat; Xenograft Model Antitumor Assays; California; pituitary adenoma; CUDC-907 (fimeprinostat); amplified luminescent proximity homogeneous assay; high throughput screen; Cushing disease; adrenocorticotropic hormone; histone deacetylase; phosphoinositide 3-kinase
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa699

Abstract
Context
Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth.
Objective
To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth.
Design
High throughput screen employing a novel “gain of signal” ACTH AlphaLISA assay.
Setting
Academic medical center.
Patients
Corticotroph tumor tissues from patients with CD.
Interventions
None.
Main outcome measures
Potent inhibitors of corticotroph tumor ACTH secretion and growth.
Results
From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion.
Conclusions
Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.