FIRST-IN-CLASS PIPELINE

Novel Antagonists Directed to Steroidogenic Factor-1 (SF-1)

 

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland with an annual incidence of 0.7-2.0 per million population. Peak incidence occurs in the fourth decade of life. Surgical resection of the tumor is the mainstay of treatment with addition of adjuvant chemotherapy. Even with complete resection, the rate of recurrence ranges from 20% to 35% in those patients with no residual disease after surgery. The only FDA-approved drug, mitotane, is difficult to dose and has significant side effects. Other chemotherapy regimens tested have been unsuccessful in improving overall survival. There is an urgent need for new therapies.

In adult ACC, expression of the orphan nuclear receptor SF-1 correlates with poor patient survival. In pediatric ACC, the gene for SF-1 is consistently amplified, strongly suggesting that SF-1 is necessary for cancer growth. SF-1 is also a driver of adrenal development. Our therapeutic hypothesis is that an SF-1 based antagonist will extend patient survival in both the pediatric and adult forms of the disease.

Orphagen has identified the first potent small molecule antagonists to SF-1. These block tumor growth in experimental xenografts derived from a patient ACC tumor. Orphagen expects to nominate a development candidate in early 2021 and to initiate clinical trials in 2022.

Additional indications for an SF-1 antagonist could include a subset of ovarian serous carcinomas (about 5% of total) where SF-1 is expressed, and endometriosis, where SF-1 is ectopically induced.

Cushing’s syndrome