ORF13-06 - Integrated Genomics, Steroidomics and High Throughput Drug Screening in a New Adrenal Cancer Cell Line (CU-ACC327) and Patient Derived Xenograft (PDX): Impact on Personalized Treatment

Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited model systems, hindering studies of tumor heterogeneity and individualized therapy.

Methods: Tumor tissue from a 44-year-old woman with a 9 cm right ACC with biochemical evidence of cortisol and androgen excess was used to establish a new immortalized cell line and a patient-derived xenograft (PDX). Model fidelity was evaluated by immunohistochemistry, short tandem repeat (STR) profiling, RNA sequencing, and whole-exome sequencing. Steroid secretion was quantified by LC-MS/MS after DMSO, ACTH, angiotensin, or forskolin treatment. Drug sensitivity was assessed by high-throughput screening MIPE 5.0 library of 2,803 cancer-related compounds and compared with standard ACC therapies across the patient’s clinical course.

Results: Pathology confirmed stage 4 oncocytic ACC with 50% Ki-67 and >20 mitoses per 50 high-power fields. Molecular testing identified TP53 (C135Y), CTNNB1 (D32N), TERT promoter (-124C>T) mutations and loss of CDKN2A loss, and MTAP. STR demonstrated a 100% match between the cell line and patient tumor and a 95% match between the PDX and patient tumor. LC-MS/MS showed baseline secretion of cortisol, DHEAS, testosterone, 11-deoxycortisol, and androstenedione; forskolin increased multiple steroids and induced estrone and corticosterone. High-throughput screen of CU-ACC327 cells identified bortezomib as a top antiproliferative hit. There was an enrichment of Proto-oncogene tyrosine-protein kinase receptor Ret Inhibitors such as Lenvatinib, while mitotane and etoposide/doxorubicin/cisplatin showed limited activity. Clinically, the patient progressed on mitotane, etoposide, doxorubicin, cisplatin, and bortezomib but responded to a combination of Lenvatinib with Pembrolizumab with a dramatic decrease in metastatic burden allowing surgical debulking.

Conclusion: CU-ACC327 is a new clinically annotated, steroidogenic ACC cell line/PDX pair. The potential combination of genomic, steroidomics and pharmacologic in vitro screening to predict patient response underscores the need for expanded ACC models and integrative approaches to translate drug testing into effective personalized treatment.