SUN-LB23 Translational Feasibility of Steroidogenic Factor-1 Antagonists as a Novel Targeted Therapy for Adrenocortical Cancer

Autor: Haiyan Tao, Neil Raheja, Scott M. Thacher, Ray Fox, Paul D. Crowe
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of the Endocrine Society
ISSN: 2472-1972
Popis: Adrenocortical carcinoma (ACC) is an aggressive cancer with devastating outcomes. ACC is usually locally advanced or metastatic at diagnosis and, despite tumor resection plus chemotherapy, has a high rate of recurrence. The 5-year survival rate among metastatic ACC patients is less than 15%. ACC responds poorly to the single FDA-approved drug, mitotane, which is non-specifically adrenolytic and highly toxic. Other chemotherapy regimens tested have been unsuccessful in improving overall survival. Steroidogenic factor-1 (SF-1 or NR5A1) is an orphan nuclear receptor essential for growth and development of the adrenal gland and is the major, active transcription factor in ACC (1,2). To address the need for a targeted therapy in ACC, we have identified potent small molecule SF-1 antagonists that block SF-1 transcriptional activity through the ligand-binding domain (IC50 = 15-20 nM in a CHO cell reporter assay). In short-term dissociated cell cultures established from SJ-ACC3 (3), a pediatric ACC patient-derived tumor xenograft (PDX), the SF-1 antagonists OR-907S and OR-070 blocked DNA synthesis as measured by inhibition of EdU incorporation in SF-1+ cells (IC50 = 500-600 nM, >80% efficacy at 10 μM) whereas OR-907R, the 100-fold less potent enantiomer of OR-907S, is nearly inactive. Because the SF-1 antagonist sensitivity of the dissociated SJ-ACC3 cells declines markedly with repeated passage of the PDX in immunocompromised (C.B-17 SCID) mice, we have utilized an alternative model system for evaluating tumor target engagement and growth inhibition: the rat Leydig tumor cell line (R2C), which is growth-inhibited by the SF-1 antagonists OR-907S and OR-070 in vitro (IC50 = 60-100 nM) and as a xenograft in immunocompromised mice (CD-1 nude). The SF-1-responsive gene signature identified by RNAseq in R2C cell cultures by comparison of OR-907S and OR-907R was replicated by OR-070 and other orally-bioavailable lead antagonists in R2C xenografts following 3 days of dosing, indicating engagement of SF-1 by these compounds. Significantly, R2C tumors were growth-inhibited following daily oral dosing for 4 weeks with OR-070 (10-30 mg/kg). These findings suggest that SF-1 antagonists could be a targeted therapy for ACC. OR-070 has >30% oral bioavailability in rat and dog, indicating that this structural class of SF-1 antagonists has potential for clinical development.References: (1) Mohan, et al., Curr. Opin. Endocrinol. Metab. Res., 2019; 8:72; (2) Corces, et al., Science, 2018; 362:eaav1898; (3) Pinto, et al., Clin. Cancer. Res., 2013; 19:1740.
Databáze: OpenAIRE
Externí odkaz: