The Journal of Clinical Endocrinology and Metabolism Journal Article

CUDC-907 as a Novel Treatment for Cushing Disease

January 18, 2021
 

Dongyun Zhang, Robert Damoiseaux, Lilit Babayan, Everett Kanediel Rivera-Meza, Yingying Yang, Marvin Bergsneider, Marilene B Wang, William H Yong, Kathleen Kelly, Anthony P Heaney
The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 1, January 2021, Pages e232–e246
https://doi.org/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.

Read the article

 

You may also like...

Publishing Benefits

Author Resource Center

We provide our journal authors with a variety of resources for increasing the discoverability and citation of their published work. Use these tools and tips to broaden the impact of your article.
Publishing Benefits

Author Resource Center

We provide our journal authors with a variety of resources for increasing the discoverability and citation of their published work. Use these tools and tips to broaden the impact of your article.

Thematic Issue

Latest Thematic Issue

immuno-endocrinology
Read our special collections of Endocrine Society journal articles, curated by topic, Altmetric Attention Scores, and Featured Article designations.

Read our special collections of Endocrine Society journal articles, curated by topic, Altmetric Attention Scores, and Featured Article designations.

Back to top
Short on time?

We'll come to you...

Get updates on the latest breakthroughs, clinical practice guidelines, and career development opportunities, straight to your inbox

Then take the next step: Set up your free website account and get exclusive access to even more great tools & content!