Use of Tyrosine Kinase Inhibitors for Treatment of Cushing's Disease and Hypercortisolism

Tech ID: fuk000432

 

Introduction

 

Cushing's Disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. No drug that effectively targets ACTH-secreting pituitary adenomas is currently approved.

 

Technology Description

 

• Inventors showed that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor.

 

• In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, inventors preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib.

 

• In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.

 

Stage of Development

 

Preclinical; in-vivo mouse data available.

 

Advantages/Novelty

 

Gefitinib (IRESSA) is a drug marketed by AstraZeneca. Gefitinib antagonizes the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to the ATP-binding site of the enzyme. On Jul 13, 2015, AstraZeneca announced that the US Food and Drug Administration (FDA) has approved Iressa (gefitinib) tablets, 250mg once daily, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test. Therefore, gefitinib has an established safety profile which will expedite drug repurposing for the new indication.

 

Applications

 

New use of the existing drug gefitinib for Cushing’s disease and hypercortisolism.

 

Intellectual Property

 

US patent 9,387,211 granted.

 

Publication

 

Fukuoka et al.  EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest. 2011;121(12):4712–4721. [Link]

 

Patent Information:
For Information, Contact:
Wenyue Du
Senior Associate - IP Management & Licensing
310-423-2241
wenyue.du@cshs.org
Inventors:
Hidenori Fukuoka
Shlomo Melmed
Keywords:
Endocrinology