Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease

  • J Clin Endocrinol Metab. 2021 Jan 1;106(1):e232-e246. doi: 10.1210/clinem/dgaa699.
Dongyun Zhang  1 ,  Robert Damoiseaux  2 ,  Lilit Babayan  1 ,  Everett Kanediel Rivera-Meza  1 ,  Yingying Yang  1 ,  Marvin Bergsneider  3 ,  Marilene B Wang  4 ,  William H Yong  5 ,  Kathleen Kelly  5 ,  Anthony P Heaney  1  3
Affiliations
  • 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.
PMID: 33000123 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.

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