Abstract 5130: Prognostic significance of loss of Cathepsin L expression in urinary bladder cancer progression

Abstract During 2021 there will be 83,730 new cases of urinary bladder cancer (UBC) in the US and 17,200 UBC deaths. Most UBC arise from the urothelial lining. UBC frequently recurs and is the most expensive cancer to treat due to the need for constant patient monitoring. New prognostic markers are needed to assist patient management. This study aims to determine if Cathepsin L is an independent prognostic factor after controlling for UBC Stage and Grade. We studied the interrelationship of Cathepsin L with Ki67, a prognostic marker in UBC. A clearer understanding of the biological mechanisms underlying UBC development and progression will lead to improved methods of UBC prognosis and suggest new therapies. Cathepsin L is a ubiquitously expressed cysteine endopeptidase capable of degrading enzymes, receptors, and transcription factors, and of activating enzymes, receptors, biologically active peptides, and pro-hormone processing by limited proteolysis. Subcellularly located in the endosomal lysosomal compartment, Cathepsin L is catalytically active at pH 3.0 - 6.5. This is a retrospective study of archived tissues and existing deidentified medical records and tumor registry information. Archived FFPE tissues were donated to Wood Hudson Cancer Research Laboratory by St. Elizabeth Healthcare (SEHC). The study was approved by the SEHC IRB. Tumors were from 41 women and 92 men. UBC were classified according to subtype, depth of invasion and grade by a Board Certified pathologist (LED). 36/62 (58.1%) of Stage 0 non-invasive UBC were Grade 1 or 2, and 26/62 (41.9%) were Grade 3 or 4. Similarly 39/90 papillary tumors (43.3%) were Grade 1 or 2 and 51/90 (36.7%) were Grade 3 or 4. In contrast 68/71 invasive UBC (Stages II, III and IV) were Grade 3 or 4. 39/90 papillary tumors were Grade 1 or 2. All non-papillary tumors were Grade 3 or 4. Ki 67 (clone MIB-1, Dako) and Cathepsin L (Abcam) expression were detected immunohistochemically. Cathepsin L was highly expressed in normal urothelium (p < 0.0001). In Stage 0, Cathepsin L expression in Grade 1,2,3 UBC was similar compared to expression in normal urothelium (p = 0.9070, 0.2560 and 0.0722). In Stage 0, Cathepsin L expression in Grade 4 UBC was significantly reduced compared to normal urothelium (p = 0.0011). Cathepsin L expression was significantly reduced in Grade 3 and 4 papillary tumors vs Grade 1 and 2 papillary tumors (p = 0.0002) and in Grade 3 and 4 non-papillary tumors vs Grade 3 and 4 papillary tumors (p = 0.0133). In each UBC subtype, grade or stage, when Cathepsin L expression was reduced cell proliferation as measured by Ki67 expression was increased and overall, this was significant (p < 0.0001). Significantly reduced Cathepsin L expression was associated with tumor recurrence and death from UBC (p = 0.03, p < 0.0001). These data suggest that when Cathepsin L is lost, intracellular levels of growth factor receptors such as EGFR may increase driving cell proliferation and UBC progression. Citation Format: Julia H. Carter, James A. Deddens, Michelle C. Robillard, Mariah K. Dooley, Daniel Stelzer, Zachary S. Taylor, Larry E. Douglass. Prognostic significance of loss of Cathepsin L expression in urinary bladder cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5130.