Bladder cancer is the fourth most common cancer in men and a significant burden for Veterans and the VHA due to the high frequency of recurrence and progression linked to smoking and exposure to deployment- related carcinogens. Nearly 80% of bladder cancers do not invade the muscle of the bladder wall (called ?non- muscle invasive bladder cancer?, NMIBC) but the most aggressive of these tumors will progress to muscle invasion with lymph node metastasis resulting in death in 30% of patients. The primary cause of death from bladder cancer is resistance to therapy as these invasive carcinomas acquire cellular plasticity and stem cell- like properties. Identification of mechanisms that regulate this change in cellular differentiation This invasive phenotype is a hallmark of cancer and a major shift in differentiation regulated by both genetic mutations and epigenetic cellular reprogramming. The long-term goal of our research is to investigate the molecular and epigenetic pathways driving invasion of bladder cancer. By understanding these mechanisms, we may develop rational and novel therapeutics for patients with bladder cancer. To investigate the epigenetic mechanisms that contribute to invasion and proliferation as a feasible target for bladder cancer, we evaluated the histone methyltransferase Enhancer of Zeste-2 (EZH2), as part of the polycomb repressor complex-2 (PRC-2) in bladder cancer. Our preliminary data demonstrate increased expression of EZH2 and its histone target, H3K27me3, in a carcinogen-induced mouse model of bladder cancer. In multiple bladder cancer cell lines, EZH2 expression is increased compared to non-transformed urothelial cells. Destabilization of the PRC-2 complex stops cellular proliferation. Consistent with our findings, bioinformatics analysis of multiple human bladder cancer databases demonstrate that EZH2 is overexpressed in invasive bladder cancers, which we have confirmed in tumor specimens from patients with all stages of bladder cancer. Given this preliminary data, our central hypothesis is that EZH2 drives invasion of bladder cancer by causing global changes in histone methylation that shifts cellular identity to an invasive and stem cell-like phenotype via an epithelial to mesenchymal transition. Thus, given our promising preliminary data, we propose to investigate our hypothesis with the following Specific Aims: 1) Determine the role of EZH2 in bladder cancer initiation and progression; 2) Investigate aberrant histone methylation of EMT, invasive and stem cell genes by EZH2 in bladder cancer; 3) Evaluate pharmacologic inhibition of EZH2 as a treatment for bladder cancer. Currently, we have no personalized genetic or epigenetic targets for bladder cancer and our best therapy for non-muscle invasive bladder cancer is > 40 years old. Through multi-disciplinary collaboration we have demonstrated feasibility with our approach. Successful completion of the studies described in this proposal will provide an innovative approach to both investigate the mechanisms involved in the invasion of bladder cancer and utilize a novel therapeutic approach to treat bladder cancer. These EZH2-targeted agents overcome the challenge of cellular resistance and have pre-clinical investigations that will allow access to Veterans with bladder cancer.

Public Health Relevance

Urothelial carcinoma (bladder cancer) is the fourth most common cancer in the VHA accounting for 7% of all cancers. More than half of bladder cancer is associated with smoking and potential deployment-related carcinogens. The majority of bladder cancer (up to 80%) is non-muscle invasive and bladder cancer remains the most costly cancer to treat due to a high frequency of both recurrence (up to 70% at five years) and progression (25% at five in high-risk patients). The long-term goal of our research is to investigate the molecular and epigenetic pathways driving invasion of bladder cancer. Our central hypothesis is that the protein Enhancer of Zeste-2 (EZH2) drives invasion of bladder cancer by causing global changes in histone methylation that shifts cellular identity to an invasive and stem cell-like phenotype via an epithelial to mesenchymal transition. In this proposal, we investigate the role of EZH2 in invasion, determine the transcriptional and histone targets, and identify novel EZH2-based therapies for treatment of Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003692-03
Application #
9605255
Study Section
Oncology A (ONCA)
Project Start
2016-10-01
Project End
2020-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Jesse Brown VA Medical Center
Department
Type
DUNS #
010299204
City
Chicago
State
IL
Country
United States
Zip Code
60612
Glaser, Alexander P; Fantini, Damiano; Wang, Yiduo et al. (2018) APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response. Oncotarget 9:4537-4548
Meeks, Joshua J; Glaser, Alexander P (2018) Editorial Comment. J Urol 200:60
Wang, Lu; Zhao, Zibo; Ozark, Patrick A et al. (2018) Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy. Nat Med 24:758-769
Weiner, Adam B; Keeter, Mary-Kate; Manjunath, Adarsh et al. (2018) Discrepancies in staging, treatment, and delays to treatment may explain disparities in bladder cancer outcomes: An update from the National Cancer Data Base (2004-2013). Urol Oncol 36:237.e9-237.e17
Fantini, Damiano; Glaser, Alexander P; Rimar, Kalen J et al. (2018) A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer. Oncogene 37:1911-1925
Fantini, Damiano; Meeks, Joshua J (2018) The BBN model: a mouse bladder cancer model featuring basal-subtype gene expression and MLL3/MLL4 genetic disruption. Oncoscience 5:172-173
Meeks, Joshua J; Lerner, Seth P (2017) Molecular Landscape of Non-Muscle Invasive Bladder Cancer. Cancer Cell 32:550-551
Meeks, Joshua J; Lerner, Seth P; Svatek, Robert S (2017) Bacillus Calmette-Guérin Manufacturing and SWOG S1602 Intergroup Clinical Trial. J Urol 197:538-540
Glaser, Alexander P; Fantini, Damiano; Shilatifard, Ali et al. (2017) The evolving genomic landscape of urothelial carcinoma. Nat Rev Urol 14:215-229
Rimar, Kalen J; Tran, Phuoc T; Matulewicz, Richard S et al. (2017) The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies. Cancer 123:1912-1924

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