Current Status and Future Targeted Therapy in Adrenocortical Cancer

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The current treatment standards include complete surgical resection for localized resectable disease and systemic therapy with mitotane alone or in combination with etoposide, doxorubicin, and cisplatin in patients with advanced ACC. However, the efficacy of systemic therapy in ACC is very limited, with high rates of toxicities. The understanding of altered molecular pathways is critically important to identify effective treatment options that currently do not exist. In this review, we discuss the results of recent advanced in molecular profiling of ACC with the focus on dysregulated pathways from various genomic and epigenetic dysregulation. We discuss the potential translational therapeutic implication of molecular alterations. In addition, we review and summarize the results of recent clinical trials and ongoing trials.

Management of adrenocortical carcinoma: are we making progress?

“…with immunotherapy), have been evaluated for ACC. 49 , 78 – 82 Targets and pathways still open for clinical exploration include the Wnt/beta-catenin signaling pathways; SF-1, as commonly over regulated transcription factor; ACAT1, an enzyme involved in the cholesterol metabolism and initially investigated for cardiovascular disease but displaying significant adrenal toxicities; the estrogen pathway, as well as FGR inhibitors. 67 , 77 Some experts have suggested that in view of the low efficacy of EDP-M, upfront targeted therapy should be discussed if a new drug or target is available, followed by EDP-M in the case of progression only.…”

Functioning metastasis from adrenocortical carcinoma

“…Due to a slower onset of action, it should be used in combination with other drugs, like metyrapone, to control significant cortisol overproduction 6. Serum levels of mitotane must be monitored and target levels are 14–20 µg/mL 1 4. Mitotane is a lipophilic molecule with a long half-life and high doses of mitotane might lead to significant adverse reactions: nausea, vomiting, diarrhoea, adrenal insufficiency, increase of hepatic enzymes, hypercholesterolemia and hypothyroidism.…”

“…In adults, ACC is mostly sporadic, although, it can be diagnosed in the context of hereditary syndromes, such as Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous polyposis and multiple endocrine neoplasia type 1 1. The prognosis of patients with ACC is generally poor, partly due to the advanced stage at diagnosis, with a median overall survival about 4 years 3 4. Most common sites of metastasis are lymph nodes, lungs, liver and bone 3.…”

“…Most common sites of metastasis are lymph nodes, lungs, liver and bone 3. The standard treatment of ACC consists in complete surgical resection for localised tumour and systemic therapy with mitotane alone or in association with etoposide, doxorubicin and cisplatin (EDP) for advanced ACC 4…”

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…Recent studies performed whole-exome sequencing (WES) on 45 and 91 ACC samples [ 5 , 6 ]. The authors report a mean somatic mutation rate of 0.6 and 0.9 mutations per megabase.…”