A Quantitative Proteo-Genomic Analysis For Targeted Therapies In The Management Of Bladder Cancer Survival

Bladder cancer is the most common type of urothelial carcinoma (UC), and it represents about 5% of all new cancers in the United States. The diagnostics, treatment, and five-year survival rates of this cancer have seen no significant improvements for nearly last three decades. Due to the lack of development of new treatment options, bladder cancer poses a bigger threat than many other cancers. In this current study, we have analyzed over 400 patients9 proteo-genomic sequencing and expression data from The Cancer Genome Atlas (TCGA) project using the cBioportal platform. We found two genes, TP53 and CDKN2A, which were significantly altered in the bladder cancer patient samples. The mutations and copy number alteration (CNA) of TP53 were present in more than 50% of patient samples, while CDKN2A was deleted in approximately 40% of patient samples. However, we found that patients with CDKN2A deletion significantly contributed to patient survival compared to TP53 mutational inactivation. Based on this finding, we further analyzed the survival associated genetic alterations in only those patient samples that have the CDK2NA deletion. Analyses indicated that bladder cancer patients with the CDKN2A gene deletion have differential expression of PIK3CA, RPS6KB1, CCND1, and TFRC and worse prognosis. Next, we analyzed protein level expression data using MD Anderson cell line project (MCLP portal) database and found that phospho-RPS6KB1 (p70-S6K_pT389) and CCND1 (Cyclin D1) were the least expressed proteins in bladder cancer cell lines compared to over fifteen different types of cancer cell lines. Additionally, data analyses of The Cancer Therapeutics Response Portal (CTRP) and MCLP database, we found two drugs- hyperforin and CD437 which have the highest Spearman9s Rho correlation with CCND1 and RPS6KB1, respectively, with significantly low p-values. Importantly, these drugs sensitize the cell lines that have low CCND1 and RPS6KB1, respectively, and would likely be beneficial for patient survival. Next, we validated our findings in three bladder cancer cell lines, T24, 5637, and HT1376. We monitored the expression of the above proteins in these bladder cancer cell-lines and compared them with other cancer cell lines. Experimental data found a strong agreement with our high throughput cell-line and patient data analysis. Besides, both hyperforin and CD437 drugs exhibit a strong cytotoxic effect on all three bladder cell lines. Furthermore, hyperforin and CD437 were found to increase the expression of CDKN2A in addition to increasing CCND1 and RPS6KB1, respectively. In summary, we characterized four different genes PIK3CA, RPS6KB1, CCND1, and TFRC, which are associated with CDKN2A mediated survival in bladder cancer. Our findings also provide a novel therapeutic approach for bladder cancer patients. Funding: This work was supported by the DoD grant to Dr. Srivastava (DAMD17-03-1-0107) and by CHIRP funding (CHIRP ID# IAA-A-HL-14-007). Disclaimers: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of The Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation (HJF), the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. *Correspondence: meera.srivastava@usuhs.edu OR alakesh.bera.ctr@usuhs.edu. Citation Format: Sreejato Chatterjee, John Karaian, Madhan Subramanian, Eric Russ, Michael Eklund, Harvey B. Pollard, Meera Srivastava, Alakesh Bera. A quantitative proteo-genomic analysis for targeted therapies in the management of bladder cancer survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4846.