OR-449, an Antagonist to Steroidogenic Factor-1 (SF-1)

Adrenocortical carcinoma (ACC) is an aggressive cancer of the adrenal gland with devastating outcomes in both adults and children. Most patients exhibit locally advanced or metastatic disease at the time of diagnosis. Tragically, the 5-year survival rate for patients with advanced ACC is <15%. Furthermore, recurrence following surgery is common and almost always fatal. The incidence of new patients is estimated to be 600 in the U.S. and 1,000 in Europe.

Orphagen has identified OR-449, a potent and selective small molecule antagonist of the orphan nuclear receptor steroidogenic factor-1 (SF-1, NR5A1), as a clinical development candidate for treatment of ACC. A Phase 1 clinical trial is projected to start in the last quarter of 2023.

SF-1 is an essential transcription factor required for the growth and development of the adrenal gland. It is highly expressed in adult ACC, and a high level of SF-1 expression is correlated with poor clinical outcome. Further, SF-1 is amplified at the chromosomal level in approximately 90% of pediatric ACC cases, indicating that elevated expression and activation of SF-1 promotes tumor growth.

Medical approaches to treat advanced ACC are only marginally beneficial and ACC patients have not experienced a major improvement in medical therapy in the last 50 years. Mitotane, the only FDA-approved drug for ACC, is poorly tolerated, difficult to dose, and has a dismal response rate. An overall effect of mitotane on patient survival is so far unproven. More intensive chemotherapy in combination with mitotane offers only limited additional benefit.

Our therapeutic hypothesis is that OR-449 will extend patient survival in both the pediatric and adult forms of ACC. Additional indications for an SF-1 antagonist may include a subset of ovarian serous or head and neck squamous cell carcinomas where SF-1 mRNA is highly expressed.

About SF-1

SF-1 is known as a master regulator of adrenocortical development and growth. SF-1 was first identified as a transcription factor binding upstream of steroid synthetic genes. SF-1 is expressed largely in steroidogenic tissues such as the adrenal cortex and gonads, but it is also expressed in a few non-steroidogenic tissues.

Overexpression of SF-1 early in development leads to ectopic adrenal tissue growth in mouse. Germline deletion of SF-1 in mice disrupts the development of the adrenal gland and other endocrine tissues, such as the gonads and pituitary gonadotrophs. Deletion of one copy of SF-1 leads to a hypofunctional adrenal gland. In combination, these results show that SF-1 can drive cell growth and phenotypic transformation.

In adult ACC, SF-1 protein expression is high, and it is a near universal marker for this cancer. Relative to a list of 1551 identified human transcription factors, SF-1 is among the five most highly expressed in one-half of all adult ACC tumors profiled in the TCGA database. Genomic studies show that SF-1, like androgen receptor in prostate cancer, is the major transcription factor in adult ACC, based both on expression and frequency of open chromatin binding sites. In adult ACC patients, there is also a consistent correlation between poor clinical outcome and higher levels of tumor SF-1 expression, quantitated either at the protein or the mRNA level.

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