Mammalian SWI/SNF complexes in urothelial bladder cancer: analysis of the tumorbiological role of ARID1A and identification of potential ARID1A-deficiency-based therapeutic strategies

• Applicant: Professor Dr. Bernhard Lüscher, since 6/2023
• Subject Area: Pathology ; Reproductive Medicine, Urology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432235170

Bladder cancer (BC) is the most common malignancy of the urinary tract. The majority of bladder tumors are non-muscle-invasive (NMI), low-grade papillary carcinomas that infrequently progress to muscle-invasive bladder cancer (MIBC) but frequently recur. In contrast, MIBC has an unfavorable prognosis and develops from high-grade (HG) lesions, most commonly via the flat-growing carcinoma in situ (CIS). BC therapy is based on aggressive treatments: high-risk NMIBC patients receive bacillus Calmette-Guérin (BCG) immunotherapy after surgical removal of the tumor, even though BCG therapy fails in >50% of cases due to toxicity or resistance. In case of BCG failure, radical cystectomy (RC) is recommended, although the rate of overtreatment is assumed to be high and RC known to cause drastic lifestyle consequences. MIBC patients are treated by RC complemented by cisplatin-based chemotherapy. Problematically, 50% of patients undergoing RC still develop metastatic disease. In the metastatic setting, a cisplatin-containing chemotherapy is indicated, although >50% of urothelial BC patients are ineligible for cisplatin treatment. Currently approved immune checkpoint inhibitors improve treatment options for metastatic BC, but the response rate is limited and responders have not yet sufficiently been defined. Thus, molecularly targeted therapies, with only minor side effects and therefore broader applicability, are needed.Subunit genes of chromatin-modifying SWI/SNF complexes, putative tumor suppressors broadly regulating the expression of differentiation and self-renewal programs and involved in DNA repair processes, are mutated in 20% across human cancers. ARID1A is the by far most frequently altered subunit gene in urothelial MIBC (~26%), with inactivating truncating mutations being the predominant mutational type. However, the urothelium-specific function of ARID1A (SWI/SNF) is to date unknown. SWI/SNF (ARID1A)-deficiency has been suggested to be a predictive marker for response to a range of therapies, including immune checkpoint inhibition. Even so, it is unclear which of these therapeutic concepts, identified in other tumor entities, might be applicable to urothelial BC.Successful identification of effective ARID1A-based therapies for urothelial BC requires an urothelium-specific understanding of SWI/SNF function. In this proposal we thus aim to decipher ARID1A-regulated pathways in the urothelium, focusing on those having established roles in carcinogenesis, to finally deduce novel therapeutic concepts for urothelial BC. We will analyze both, transcriptionally ARID1A-regulated pathways and the ARID1A interactome. Moreover, we aim to validate the potential of ARID1A-deficiency as candidate predictive biomarker for the recently approved immune checkpoint inhibitors in urothelial BC.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Stefan Garczyk, until 5/2023