Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease

Author:

Zhang Dongyun1,Damoiseaux Robert2,Babayan Lilit1,Rivera-Meza Everett Kanediel1,Yang Yingying1,Bergsneider Marvin3,Wang Marilene B4,Yong William H5,Kelly Kathleen5,Heaney Anthony P13ORCID

Affiliation:

1. Department of Medicine, University of California, David Geffen School of Medicine, Los Angeles, California

2. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California

3. Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California

4. Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, California

5. Department of Pathology and Lab Medicine, David Geffen School of Medicine, University of California, Los Angeles, California

Abstract

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.

Funder

Multi-campus Research Programs and Initiatives of the UC Office of the President

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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