Targeting the expression of T antigens with Selinexor (KPT‐330) shows promise for MCPyV‐positive Merkel cell carcinoma treatment

2021 ◽  
Author(s):  
R. Gupta ◽  
R.A. Simonette ◽  
H.Q. Doan ◽  
P.L. Rady ◽  
S.K. Tyring
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Merkel Cell ◽  
T Antigens

scholarly journals Mechanisms of p53 Restriction in Merkel Cell Carcinoma Cells Are Independent of the Merkel Cell Polyoma Virus T Antigens

2013 ◽  
Vol 133 (10) ◽  
pp. 2453-2460 ◽  
Author(s):  
Roland Houben ◽  
Christina Dreher ◽  
Sabrina Angermeyer ◽  
Andreas Borst ◽  
Jochen Utikal ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Polyoma Virus ◽  
Carcinoma Cells ◽  
Merkel Cell ◽  
T Antigens ◽  
Merkel Cell Polyoma Virus

scholarly journals Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 919 ◽  
Author(s):  
Bhavishya Sarma ◽  
Christoph Willmes ◽  
Laura Angerer ◽  
Christian Adam ◽  
Jürgen C. Becker ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Antigen Expression ◽  
T Antigen ◽  
Merkel Cell ◽  
T Antigens ◽  
Growth And Survival ◽  
Proliferative Effect

Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate—a drug used to treat malaria—has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.

scholarly journals Type I and II IFNs Inhibit Merkel Cell Carcinoma via Modulation of the Merkel Cell Polyomavirus T Antigens

2012 ◽  
Vol 72 (8) ◽  
pp. 2120-2128 ◽  
Author(s):  
Christoph Willmes ◽  
Christian Adam ◽  
Miriam Alb ◽  
Lena Völkert ◽  
Roland Houben ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Merkel Cell Polyomavirus ◽  
Type I ◽  
Merkel Cell ◽  
T Antigens

scholarly journals Merkel Cell Polyomavirus-Infected Merkel Cell Carcinoma Cells Require Expression of Viral T Antigens

2010 ◽  
Vol 84 (14) ◽  
pp. 7064-7072 ◽  
Author(s):  
Roland Houben ◽  
Masahiro Shuda ◽  
Rita Weinkam ◽  
David Schrama ◽  
Huichen Feng ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Cell Lines ◽  
Merkel Cell Carcinoma ◽  
Annexin V ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
T Antigens ◽  
Negative Cell ◽  
Exon 1

ABSTRACT Merkel cell carcinoma (MCC) is the most aggressive skin cancer. Recently, it was demonstrated that human Merkel cell polyomavirus (MCV) is clonally integrated in ∼80% of MCC tumors. However, direct evidence for whether oncogenic viral proteins are needed for the maintenance of MCC cells is still missing. To address this question, we knocked down MCV T-antigen (TA) expression in MCV-positive MCC cell lines using three different short hairpin RNA (shRNA)-expressing vectors targeting exon 1 of the TAs. The MCC cell lines used include three newly generated MCV-infected cell lines and one MCV-negative cell line from MCC tumors. Notably, all MCV-positive MCC cell lines underwent growth arrest and/or cell death upon TA knockdown, whereas the proliferation of MCV-negative cell lines remained unaffected. Despite an increase in the number of annexin V-positive, 7-amino-actinomycin D (7-AAD)-negative cells upon TA knockdown, activation of caspases or changes in the expression and phosphorylation of Bcl-2 family members were not consistently detected after TA suppression. Our study provides the first direct experimental evidence that TA expression is necessary for the maintenance of MCV-positive MCC and that MCV is the infectious cause of MCV-positive MCC.

Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma

2016 ◽  
Vol 174 (4) ◽  
pp. 813-822 ◽  
Author(s):  
M. Samimi ◽  
L. Molet ◽  
M. Fleury ◽  
H. Laude ◽  
A. Carlotti ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Prognostic Value ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
T Antigens ◽  
Vp1 Protein

scholarly journals Targeting Merkel Cell Carcinoma by Engineered T Cells Specific to T-Antigens of Merkel Cell Polyomavirus

2018 ◽  
Vol 24 (15) ◽  
pp. 3644-3655 ◽  
Author(s):  
Ioannis Gavvovidis ◽  
Matthias Leisegang ◽  
Gerald Willimsky ◽  
Natalie Miller ◽  
Paul Nghiem ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
T Antigens ◽  
Engineered T Cells
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