Significance of ubiquitin-proteasome system elements as therapeutic targets in advanced penile carcinoma in elderly patients

• Applicant: Dr. Anita Thomas
• Subject Area: Reproductive Medicine, Urology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511954268

Penile cancer is an extremely aggressive disease for which there are no effective treatment options available in the metastatic stage. For the treatment of systemic disseminated disease, very limited data exists on cisplatin-based protocols. However, treatment resistance develops rapidly, resulting in most regimens being associated with a response rate of only 30%. In the case of re-progression, there are no established second-line protocols available.In terms of disease progression, older patients with penile cancer are at a particular disadvantage. Since cisplatin-based protocols are associated with a not negligible toxicity rate and are thus often not suitable for elderly patients, there is an explicit demand for personalized and tailored treatment concepts especially for this target population. In this regard, the ubiquitin-proteasome system is becoming the focus of research activities in the field of targeted therapy for advanced penile cancer. In recent years, there has been increasing evidence that proteasome activity decreases during aging in various model systems and that these changes may be causally related to aging and age-related diseases as well as to squamous cell carcinoma tumorigenesis. Elaboration of the molecular apparatus of the ubiquitin system appears promising in penile carcinoma in order to identify the components involved in tumorigenesis and for further investigation of their therapeutic potential.Within the scope of the envisaged research project, sequencing of penile cancer tumor tissue and adjacent normal tissue at the transcriptional level of mRNAs is planned. Based on preliminary studies, we hypothesize that the profile of deregulated mRNAs will be differentially expressed in penile carcinomas based on age (patients < 70 years vs. patients ≥ 70 years based on the median age of onset for the disease). Hereafter, the most up- and down-regulated mRNAs of the ubiquitin-proteasome system and associated kinases will be extracted by biostatistical methods and selected for further analysis. Here, particular attention will be paid to the detectable deregulations in the older patient cohort. Subsequently, drugs with promising efficacy in the ubiquitin-proteasome system and associated kinases will be identified and tested in penile cancer cell lines. Thus, the research project opens for the first time the possibility of testing novel clinically relevant personalized treatment approaches in advanced penile cancer and for the aging patient a tailored therapeutic approach.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Krishnaraj Rajalingam; Professor Dr. Igor Tsaur