TY  - JOUR
A1  - Thomas, Anita
A1  - Reetz, Sascha
A1  - Stenzel, Philipp J.
A1  - Tagscherer, Katrin
A1  - Roth, Wilfried
A1  - Schindeldecker, Mario
A1  - Michaelis, Martin
A1  - Rothweiler, Florian
A1  - Cinatl, Jindrich
A1  - Cinatl, Jaroslav
A1  - Dotzauer, Robert Hans
A1  - Vakhrusheva, Olesya
A1  - Albersen, Maarten
A1  - Macher-Göppinger, Stephan
A1  - Haferkamp, Axel
A1  - Jüngel, Eva
A1  - Neisius, Andreas
A1  - Tsaur, Igor
T1  - Assessment of PI3K/mTOR/AKT pathway elements to serve as biomarkers and therapeutic targets in penile cancer
T2  - Cancers
N2  - Simple Summary: Penile cancer is a rare but aggressive malignancy characterized by rapid tumor growth as well as prompt metastasis in groin lymphatics. While localized diseases can be successfully cured by surgery in most cases, no truly effective treatment options have been established for metastatic diseases as of yet. In the current investigation, we assessed the value of selected members of the PI3K/mTOR/AKT pathway to serve as tumor markers or therapeutic targets for this disease. Higher expression of AKT was significantly more prevalent in high-grade tumors and independently predictive of the worse survival parameters, while increased expression of pmTOR was associated with an inferior prognosis as well. Treatment with the pan-AKT inhibitor capivasertib in PeCa cell lines induced significant reduction of cell viability and movement capacity. These findings might aid in the understanding of the molecular tumor background as well as development of novel treatment options for advanced penile cancer.

Abstract: The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.
KW  - penile cancer
KW  - AKT
KW  - mTOR
KW  - cell lines
KW  - biomarker
KW  - targeted therapy
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62112
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-621126
SN  - 2072-6694
VL  - 13
IS  - 10, art. 2323
SP  - 1
EP  - 18
PB  - MDPI
CY  - Basel
ER  -