Browsing by Subject "Tumour-suppressor proteins"

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    Effective combinatorial immunotherapy for penile squamous cell carcinoma
    (Springer Nature, 2020-05-01) Huang, Tianhe; Cheng, Xi; Chahoud, Jad; Sarhan, Ahmed; Tamboli, Pheroze; Rao, Priya; Guo, Ming; Manyam, Ganiraju; Zhang, Li; Xiang, Yu; Han, Leng; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Lu, Xuemin; Feng, Shan; Ferrer, Magaly Martinez; Wang, Y. Alan; DePinho, Ronald A.; Pettaway, Curtis A.; Lu, Xin; Medicine, School of Medicine
    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.