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Project

Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

Funder: National Cancer Institute

Funding period
USD 243 K
Funding amount
Abstract
Project Summary and Abstract The overall goal of this proposal is to support the training of Dr. Byron Lee to become an independent investigator conducting translational research in bladder cancer epigenomics. Dr. Lee will be mentored by Dr. Nima Sharifi and Dr. Peter Scacheri. Dr. Nima Sharifi is the leader of the Genitourinary Malignancies Program at the Case Comprehensive Cancer Center and has mentored numerous young physician-scientists. Dr. Peter Scacheri is Professor of Genetics at Case Western Reserve University and an expert in cancer epigenomics. The training plan incorporates the following goals: (1) enhance understanding of chromatin biology, (2) gain expertise in bioinformatics analysis of complex biological data, and (3) develop proficiency in the use of patient-derived samples for translational research. Bladder cancer is the fifth most common non-cutaneous malignancy in the United States, yet few new treatment options exist. The Cancer Genome Atlas (TCGA), a large-scale effort supported by NCI and NHGRI to determine the molecular basis of cancer, performed comprehensive molecular characterization of over 400 muscle invasive bladder cancers and showed that chromatin modifier gene alterations occur in 75% of cases. Most of these alterations are predicted to result in loss of function; however, their effects on bladder cancer initiation, progression, and response to therapy are largely unknown. These genes alter the configuration of the DNA-histone interface, which affects the ability of DNA-binding proteins to access their target sequences. The central hypothesis that will be tested is that chromatin modifier gene mutation leads to gene expression changes that support bladder cancer initiation and progression through enhancer disruption. To accomplish this goal, we propose the following Specific Aims: (1) Test the hypothesis that KDM6A inactivation alters the chromatin state of urothelial cells and engenders a transcriptional program that results in neoplastic growth, and (2) Test the hypothesis that enhancer dysfunction and aberrant transcriptional circuits characterize human bladder cancer and dependence on these circuits for growth result in vulnerability to existing targeted therapies. Successful completion of the proposed research will advance our understanding of how chromatin modifier gene mutations, one of the most frequent somatic alterations in bladder cancer, affect disease initiation and progression. Moreover, we expect to identify molecular vulnerabilities arising from enhancer disruption and changes in transcription factor circuits. Targeting these vulnerabilities can lead to the development of novel therapies for bladder cancer.

 
408
Projects
USD 265.3 M
Aggregated funding amount
USD 700 K
Average funding amount
Project list item
Investigating underlying molecular mechanisms of epigenetic therapies in muscle-invasive bladder cancer

Bladder Cancer Advocacy Network to Swathi Ramakrishnan

USD 1,700
2019 - 2019
Project list item
DNA adductome of human bladder from the tobacco exposome

National Institute of Environmental Health Sciences to ROBERT J. TURESKY

USD 467,974
2019 - 2023
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Combatting Bladder Cancer by Inducing Epithelial Turnover

National Cancer Institute to SOMAN N ABRAHAM

USD 203,510
2019 - 2021
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Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

National Cancer Institute to HIKMAT AL-AHMADIE

USD 410,835
2019 - 2024
Project list item
The role of a new molecular driver in bladder cancer

National Cancer Institute to DALEY MORERA

USD 45,016
2018 - 2021
Project list item
Identifying DNA Biomarkers of Bacillus Calmette-Guerin (BCG) Resistance in Non-Muscle-Invasive Bladder Cancer

Canadian Institutes of Health Research to Jack Victor Warren Bacon, Alexander William Wyatt

USD 847
2018 - 2019
Project list item
Novel 3D personalized bladder cancer model on demand: A new era for personalized medicine.

Canadian Institutes of Health Research to Alan I So, Claudia Itze Chavez-munoz

USD 141,091
2018 - 2020
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
Elucidating immunotherapy resistance mechanisms in non-T cell-inflamed bladder cancer

National Cancer Institute to RANDY F. SWEIS

USD 212,669
2018 - 2022
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
SPORE in Bladder Cancer

National Cancer Institute to DEAN F. BAJORIN, TIMOTHY AN-THY CHAN, IRINA OSTROVNAYA, HIKMAT AL-AHMADIE, MICHAEL STEPHEN GLICKMAN, DAVID B SOLIT

USD 2,299,837
2018 - 2023
Project list item
Modeling bladder cancer metastasis using human patient-derived tumor organoids

Bladder Cancer Advocacy Network to Michael M Shen

USD 300,000
2018 - 2020
Project list item
Upper tract urothelial carcinoma is non-basal and T-cell depleted

Bladder Cancer Advocacy Network to Panagiotis Vlachostergios

USD 1,700
2018 - 2018
Project list item
Unraveling disparate roles of Notch-1 and Notch-2 signaling in bladder cancer.

Michael Smith Foundation for Health Research to Peter C Black

USD 338,302
2018 - 2023
Project list item
Circulating tumor DNA as a predictive biomarker in metastatic bladder cancer

Canadian Institutes of Health Research to Gillian Rae Vandekerkhove, Alexander William Wyatt

USD 53,221
2018 - 2021
Project list item
Challenging dogma: an alternative non-hierarchical, epigenetically regulated model of the urothelium.

Biotechnology and Biological Sciences Research Council to Andrew Feber

USD 468,019
2018 - 2021
Project list item
Challenging dogma: an alternative non-hierarchical, epigenetically regulated model of the urothelium.

Biotechnology and Biological Sciences Research Council to Jennifer Southgate

USD 605,256
2018 - 2021
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