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Similar Projects for

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.

 
49
Projects
USD 15.4 M
Aggregated funding amount
USD 386 K
Average funding amount
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, HIKMAT AL-AHMADIE, MICHAEL M. SHEN

USD 1,765,498
2018 - 2023
Project list item
Novel recombinant BCG for immunotherapy of bladder cancer

National Cancer Institute to BORIS SHOR

USD 290,014
2018 - 2019
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
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 - 2019
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
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
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
Project list item
Synergistic Immuno-Photo-Nanotherapy for Bladder Cancer

Congressionally Directed Medical Research Programs to Brant A. Inman

USD 624,398
2015 - 2016
Project list item
The Role of ATM Loss and the ATR-CHK1 Pathway in Bladder Cancer

Bladder Cancer Advocacy Network to Rahul Parikh, Susanne M. Gollin, Leonard J. Appleman, Hong Wang, Rajiv Dhir

USD 100,000
2015 - 2018
Project list item
Analysis of newly detected serum protein and trial of establishment of diagnostic tool in patients with bladder cancer

Japan Society for the Promotion of Science to Kazumasa MATSUMOTO, Yuichi SATO, Masatsugu IWAMURA

USD 42,591
2015 - 2018
Project list item
Antitumor effect by regulation of EZH2 on urothelial carcinoma

Japan Society for the Promotion of Science to NOZOMI HAYAKAWA, Eiji KIKUCHI, Akira MIYAJIMA, Mototsugu OYA

USD 35,497
2015 - 2017
Project list item
Functional characterization of novel non-coding RNA transcripts in bladder cancer

Canadian Institutes of Health Research to Adrian Dilan Gunaratne, Jeffrey L. Wrana

USD 16,953
2015 - 2015
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