Genetic Data Points to Potential New Therapeutic Target for Adrenocortical Carcinoma

According to study results presented at the 21st Annual Congress of the American Association of Clinical Endocrinologists, overexpression of pituitary tumor transforming gene 1 (PTTG1) is associated with low survival rates in patients with adrenocortical carcinoma (ACC). However, treatment with vorinostat, which decreases PTTG1 expression, may be suitable for targeted treatment of ACC.

Researchers extracted RNA from 100 mg samples from 19 flash-frozen ACC tumors, along with RNA from four normal adrenal glands. Sixty-three percent of the patients from whom the tumors were extracted were female, with an average age of 47.6 years. Median survival was 5.9 years. The average tumor size was 9.7 cm and 351 g.

Using gene expression profiling, the authors examined the samples and “identified marked dysregulation of the cell cycle control, focused on sister chromatid adhesion and cytokinesis in the G2/M transition.” In particular, they reported potential alterations in activity of the tumor suppressor gene p53, noting that “genes that are normally repressed by p53 were overexpressed, and those that are normally promoted had decreased expression.”

The researchers identified overexpression of PTTG1, which encodes the antibody securin, “a negative regulator of p53 and a protein involved in the G2/M transition,” as a marker of poor survival. Patients with tumors expressing high levels of PTTG1 levels had a median survival of 1.2 years, whereas patients with tumors expressing lower levels of PTTG1 had a median survival of 9.8 years.

Treating two ACC cell lines (SW-13 and H295R) with the histone deacytlase inhibitor vorinostat “decreased securin levels in both cell lines and inhibited cell growth with IC50 values of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively.”

This may be a potentially promising development because, as the authors noted, ACC “is an aggressive malignancy with poor overall five-year survival (16-22%).” Complete surgical excision is the only current treatment with the potential to cure ACC. However, up to 70% of patients have metastases at the time of diagnosis, ruling out surgery. Current chemotherapy options are limited for ACC—the antineoplastic drug mitotane has only a 25% response rate. In the recently concluded FIRM-ACT study, patients with ACC treated with a regimen of etoposide, doxorubicin, cisplatin, and mitotane had a median overall survival of 14.8 months. The response rate for this regimen was only 24%.

The authors noted that limited options currently available to patients with ACC underscore the “continued need to understand the underlying molecular pathogenesis of ACC and develop new therapies.” Further study of the effect of overexpression of PTTG1 on survival in ACC and the potential of vorinostat to inhibit cell growth is warranted.