Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease.

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.