TY  - JOUR
A1  - Ronchi, Cristina L.
A1  - Sbiera, Silviu
A1  - Volante, Marco
A1  - Steinhauer, Sonja
A1  - Scott-Wild, Vanessa
A1  - Altieri, Barbara
A1  - Kroiss, Matthias
A1  - Bala, Margarita
A1  - Papotti, Mauro
A1  - Deutschbein, Timo
A1  - Terzolo, Massimo
A1  - Fassnacht, Martin
A1  - Allolio, Bruno
T1  - CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma
N2  - Background

Adrenocortical 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.

Objective

To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.

Material and Methods

CYP2W1 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).

Conclusion

CYP2W1 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.
KW  - CYP2W1
KW  - cancer treatment
KW  - adrenal glands
KW  - carcinomas
KW  - drug therapy
KW  - hormones
KW  - immune response
KW  - immunohistochemistry techniques
KW  - surgical oncology
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113096
ER  - 
TY  - JOUR
A1  - Rasche, Leo
A1  - Duell, Johannes
A1  - Morgner, Charlotte
A1  - Chatterjee, Manik
A1  - Hensel, Frank
A1  - Rosenwald, Andreas
A1  - Einsele, Hermann
A1  - Topp, Max S.
A1  - Brändlein, Stephanie
T1  - The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78
JF  - PLoS ONE
N2  - In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.
KW  - cytotoxicity
KW  - apoptosis
KW  - immunohistochemistry techniques
KW  - enzyme-linked immunoassays
KW  - multiple myeloma
KW  - cell staining
KW  - cell binding
KW  - complement system
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130125
VL  - 8
IS  - 5
ER  -