Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease

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.

Keywords: CUDC-907 (fimeprinostat); Cushing disease; adrenocorticotropic hormone; amplified luminescent proximity homogeneous assay; high throughput screen; histone deacetylase; phosphoinositide 3-kinase; pituitary adenoma.