TY - JOUR
T1 - Transcriptome-Guided Drug Repurposing for Aggressive SCCs
AU - Zauner, Roland
AU - Wimmer, Monika
AU - Dorfer, Sonja
AU - Ablinger, Michael
AU - Koller, Ulrich
AU - Piñón Hofbauer, Josefina
AU - Guttmann-Gruber, Christina
AU - Bauer, Johann
AU - Wally, Verena
N1 - Zauner, Wimmer, Dorfer, Ablinger, Koller, Piñón Hofbauer, Guttmann-Gruber, Bauer, Wally: EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; Bauer: Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
PY - 2022/1/17
Y1 - 2022/1/17
N2 - Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa (RDEB), SCCs arise more frequently and follow a particularly aggressive course. Notably, such SCC types display molecular similarities, despite their differing etiologies. We leveraged the similarities in transcriptomes between tumors from organ transplant recipients and RDEB-patients, augmented with data from more common head and neck (HN)-SCCs, to identify drugs that can be repurposed to treat these SCCs. The in silico approach used is based on the assumption that SCC-derived transcriptome profiles reflect critical tumor pathways that, if reversed towards healthy tissue, will attenuate the malignant phenotype. We determined tumor-specific signatures based on differentially expressed genes, which were then used to mine drug-perturbation data. By leveraging recent efforts in the systematic profiling and cataloguing of thousands of small molecule compounds, we identified drugs including selumetinib that specifically target key molecules within the MEK signaling cascade, representing candidates with the potential to be effective in the treatment of these rare and aggressive SCCs.
AB - Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa (RDEB), SCCs arise more frequently and follow a particularly aggressive course. Notably, such SCC types display molecular similarities, despite their differing etiologies. We leveraged the similarities in transcriptomes between tumors from organ transplant recipients and RDEB-patients, augmented with data from more common head and neck (HN)-SCCs, to identify drugs that can be repurposed to treat these SCCs. The in silico approach used is based on the assumption that SCC-derived transcriptome profiles reflect critical tumor pathways that, if reversed towards healthy tissue, will attenuate the malignant phenotype. We determined tumor-specific signatures based on differentially expressed genes, which were then used to mine drug-perturbation data. By leveraging recent efforts in the systematic profiling and cataloguing of thousands of small molecule compounds, we identified drugs including selumetinib that specifically target key molecules within the MEK signaling cascade, representing candidates with the potential to be effective in the treatment of these rare and aggressive SCCs.
KW - SQUAMOUS-CELL CARCINOMA
KW - EPIDERMOLYSIS-BULLOSA
KW - SKIN CANCERS
KW - PAPILLOMAVIRUS
KW - INTEGRATION
KW - EXPRESSION
KW - PACKAGE
KW - TARGETS
U2 - 10.3390/ijms23021007
DO - 10.3390/ijms23021007
M3 - Original Article (Journal)
C2 - 35055192
SN - 1422-0067
VL - 23
JO - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
IS - 2
ER -