CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma

Abstract

BackgroundAdrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.ObjectiveTo investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.Material and MethodsCYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples).Results CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0–1) in 72% of non-adrenal normal tissues, but high (H-score 2–3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01).ConclusionCYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.

Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A 13-Institution Study by the US Adrenocortical Carcinoma Group

“…Beyond targeting the tumor and the tumor environment, assessing the metabolic profile of patients with ACC could guide therapy, as drug metabolism could be intimately related to response to therapy. 39 …”

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

“…Patients with tumors that had CYP2W1 immunoreactivity showed, when adjusted for ENSAT stage, a longer overall survival and time to progression when treated with mitotane monotherapy. This difference was not present in patients who only underwent follow-up (Ronchi et al 2014b). Ribonucleotide reductase large subunit 1 (RRM1) gene expression was associated with a shorter disease-free survival and overall survival .…”

“…Recently, several studies have identified potential factors associated with response to mitotane, such as CYP2W1 (Ronchi et al 2014b). Patients with tumors that had CYP2W1 immunoreactivity showed, when adjusted for ENSAT stage, a longer overall survival and time to progression when treated with mitotane monotherapy.…”

The CYP2W1 enzyme: regulation, properties and activation of prodrugs

“…Thus, the Protein Atlas produced polyclonal antibodies distributed through the Sigma-Aldrich (www.proteinatlas.org) show CYP2W1 expression in almost every normal human tissue, which is not supported neither by mRNA nor by protein expression data using different antibodies. Furthermore, CYP2W1 protein has been claimed to be present in, for example MCF-7 cells (Tan et al, 2011) and in the normal adrenal glands (Ronchi et al, 2014); however, using 852 Ab antibody we see no protein expression (Nol e P et al, unpublished observations). Similarly, the data on the expression of CYP2W1 protein in adenocarcinoma, childhood rhabdomyosarcoma, breast cancer should be taken with certain degree of caution and validated using different antibodies.…”