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Project

Investigating underlying molecular mechanisms of epigenetic therapies in muscle-invasive bladder cancer

Funder: Bladder Cancer Advocacy Network

Funding period
USD 2 K
Funding amount
Abstract
Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose non-fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of zeste homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2 based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-?). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1a, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death.

 
62
Projects
USD 24.4 M
Aggregated funding amount
USD 498 K
Average funding amount
Project list item
Roles of epigenetic regulators in bladder cancer progression

University of California - Cancer Research Coordinating Committee to Zhu Wang

USD 74,960
2020 - 2020
Project list item
Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

National Cancer Institute to BYRON H LEE

USD 243,205
2019 - 2024
Project list item
Modeling bladder cancer pathogenesis and tumor evolution

National Cancer Institute to CORY ABATE-SHEN, DAVID B SOLIT, MICHAEL M. SHEN, HIKMAT AL-AHMADIE

USD 3,432,927
2018 - 2023
Project list item
Novel recombinant BCG for immunotherapy of bladder cancer

National Cancer Institute to BORIS SHOR

USD 290,014
2018 - 2020
Project list item
Role of B-arrestins in bladder cancer progression and response to chemotherapy

United States Department of Veterans Affairs to BAL L LOKESHWAR

 
2018 - 2022
Project list item
Dissection of Suppressive Axes Underlying Natural Killer Cell Dysfunction in Human Bladder Cancer

Congressionally Directed Medical Research Programs to Nina Bhardwaj

USD 1,584,753
2017 - 2018
Project list item
Dissection of Suppressive Axes Underlying Natural Killer Cell Dysfunction in Human Bladder Cancer

Congressionally Directed Medical Research Programs to John Sfakianos

USD 109,710
2017 - 2018
Project list item
Targeting the Regulation and Actions of Telomerase Reverse Transcriptase (TERT) in Bladder Cancer

Congressionally Directed Medical Research Programs to Dan Theodorescu

USD 1,482,998
2017 - 2018
Project list item
Proteogenomic characterization of muscle invasive bladder cancer to identify mechanisms of resistance and targets for therapy

Bladder Cancer Advocacy Network to Seth P. Lerner, Susan Hilsenbeck, Matthew James Ellis, Keith Syson Chan, Jonathan Michael Levitt, Sung Yun Jung, Anna Malovannaya, Bing Zhang

USD 300,000
2017 - 2020
Project list item
Innate effector cells in bladder carcinogenesis

Bladder Cancer Advocacy Network to Neelam Mukherjee

USD 1,700
2017 - 2017
Project list item
Defining the Immune Response to Chemotherapy and Chemo-Immunotherapy in Muscle-Invasive Bladder Cancer

Bladder Cancer Advocacy Network to Tracy L Rose, William Youngkwan Kim, Matthew Milowsky, Benjamin Vincent

USD 50,000
2017 - 2018
Project list item
The Role of EZH2 in Non-Muscle Invasive Bladder Cancer

United States Department of Veterans Affairs to JOSHUA JAMES MEEKS

 
2016 - 2020
Project list item
Sh3gl2 and chemosensitivity of bladder cancer

National Cancer Institute to ROSALYN M ADAM

USD 492,035
2016 - 2019
Project list item
Targeting FGFR3 in muscle-invasive bladder cancer.

Bladder Cancer Advocacy Network to David J. McConkey, Colin P Dinney, Charles G Drake, Bogdan Czerniak, woonyoung choi, Trinity Bivalacqua, Noah M. Hahn, Arlene O Siefker-Radtke

USD 299,720
2016 - 2019
Project list item
Study of the KMT2C/MLL3 role in bladder cancer

Worldwide Cancer Research to Apostolos Klinakis

USD 203,631
2016 - 2019
Project list item
Elucidation of epigenome-mediated proliferation mechanism in bladder cancer and development of therapy with novel inhibitors

Japan Society for the Promotion of Science to Keitaro Iida, Noriyasu KAWAI, Takayoshi SUZUKI, Ryosuke Ando, Toshiki ETANI, Takahiro YASUI, Taku NAIKI

USD 35,243
2016 - 2018
Project list item
Precision Medicine in Platinum-Treated Lethal Bladder Cancer

Congressionally Directed Medical Research Programs to Jonathan Rosenberg

USD 788,605
2015 - 2016
Project list item
Precision Medicine in Platinum-Treated Lethal Bladder Cancer

Congressionally Directed Medical Research Programs to David Mcconkey

USD 411,266
2015 - 2016
Project list item
Precision Medicine in Platinum-Treated Lethal Bladder Cancer

Congressionally Directed Medical Research Programs to Eliezer M Van allen

USD 346,210
2015 - 2016
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