Abstract
Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
Highlights
The genetically engineered mouse (GEM) model of Penile squamous cell carcinoma (PSCC) in our studies is based on the use of PB-Cre[4] as the Cre driver in Androgen receptor (AR)-expressed androgenresponsive epithelial cells of the mouse penis
Our models indicate that the androgen-sensitive epithelial cells are the potential cells of origin for PSCC, AR expression is unlikely to be essential for sustaining tumorigenesis based on its diminished level in established PSCC (Fig. 1a)
It is worth noting that activation of WNT/β-catenin targets may be achieved through various mechanisms
Summary
Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. The generation of genetically engineered mouse (GEM) models of PSCC has not been reported. Patients whose PSCC progresses or recurs after front-line cisplatin-based chemotherapy experience poor responses to salvage treatments (OS < 6 months)[13]. Developing resources for PSCC such as GEM models will be critical to evaluate the efficacy of ICB in a meaningful preclinical setting and, perhaps more importantly, to predict potential resistance mechanisms for ICB and design corresponding combination therapy strategies. Intratumoral immunosuppressive myeloid cell infiltration suggests the benefit of combining targeted therapy and immunotherapy to achieve maximal clinical efficacy. This illuminates a testable clinical trial hypothesis for combination therapy in the treatment of lethal PSCC
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.