TY  - JOUR
A1  - Esnault, Clara
A1  - Schrama, David
A1  - Houben, Roland
A1  - Guyétant, Serge
A1  - Desgranges, Audrey
A1  - Martin, Camille
A1  - Berthon, Patricia
A1  - Viaud-Massuard, Marie-Claude
A1  - Touzé, Antoine
A1  - Kervarrec, Thibault
A1  - Samimi, Mahtab
T1  - Antibody–drug conjugates as an emerging therapy in oncodermatology
JF  - Cancers
N2  - Antibody–drug conjugates (ADCs) are an emerging class of therapeutics, with twelve FDA- and EMA-approved drugs for hematological and solid cancers. Such drugs consist in a monoclonal antibody linked to a cytotoxic agent, allowing a specific cytotoxicity to tumor cells. In recent years, tremendous progress has been observed in therapeutic approaches for advanced skin cancer patients. In this regard, targeted therapies (e.g., kinase inhibitors) or immune checkpoint-blocking antibodies outperformed conventional chemotherapy, with proven benefit to survival. Nevertheless, primary and acquired resistances as well as adverse events remain limitations of these therapies. Therefore, ADCs appear as an emerging therapeutic option in oncodermatology. After providing an overview of ADC design and development, the goal of this article is to review the potential ADC indications in the field of oncodermatology.
KW  - antibody–drug conjugates
KW  - oncodermatology
KW  - melanoma
KW  - skin squamous cell carcinoma
KW  - cutaneous T-cell lymphoma and Merkel cell carcinoma
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262192
SN  - 2072-6694
VL  - 14
IS  - 3
ER  - 
TY  - JOUR
A1  - Grimm, Johannes
A1  - Hufnagel, Anita
A1  - Wobser, Marion
A1  - Borst, Andreas
A1  - Haferkamp, Sebastian
A1  - Houben, Roland
A1  - Meierjohann, Svenja
T1  - BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1
JF  - Oncogenesis
N2  - Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.
KW  - melanoma
KW  - senescence
KW  - BRAF
KW  - tumor
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177261
VL  - 7
IS  - 71
ER  - 
TY  - JOUR
A1  - Hafner, Christian
A1  - Houben, Roland
A1  - Baeurle, Anne
A1  - Ritter, Cathrin
A1  - Schrama, David
A1  - Landthaler, Michael
A1  - Becker, Jürgen C.
T1  - Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma
JF  - PLoS One
N2  - Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.
KW  - rare
KW  - T-antigen
KW  - PIK3CA mutations
KW  - squamous cell
KW  - melanoma
KW  - polymavirus
KW  - cancer
KW  - tumors
KW  - akt
KW  - expression
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131398
VL  - 7
IS  - 2
ER  -