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Similar Projects for

Project

Elucidating immunotherapy resistance mechanisms in non-T cell-inflamed bladder cancer

Funder: National Cancer Institute

Funding period
USD 425 K
Funding amount
Abstract
PROJECT SUMMARY Muscle invasive urothelial bladder cancer is a clinically aggressive disease with poor outcomes despite modern therapies. Recently, antibodies targeting the PD-1/PD-L1 immune checkpoint pathway have shown efficacy and were approved for use for locally advanced or metastatic bladder cancer. In some patients, impressive and durable clinical responses are observed, yet the rate of response remains modest at 20%. Mechanisms of pri- mary immune resistance in bladder cancer are not fully understood. The presence of a T cell-inflamed tumor phenotype has been associated with improved survival and response to immunotherapies. T cell-inflamed tu- mors can be identified by the presence of intratumoral CD8+ T cells or expression of a T cell gene signature. Emerging data have indicated that certain oncogenic pathways, such as FGFR3, are activated exclusively in non-T cell-inflamed bladder cancers. The underlying hypothesis of this proposal is that FGFR3 activation pre- vents spontaneous T cell priming in bladder cancer and may be therapeutically targeted to restore sensitivity to immune checkpoint blockade. A mechanistic investigation into the immunomodulatory effects of FGFR3 will be pursued through (a) a new genetically-engineered mouse model system with tamoxifen-inducible KrasG12D/p53fl/fl carcinomas that also express an activating FGFR3K644E mutation, (b) a syngeneic transplantable mouse model system using the MB49 bladder cancer cell line with model antigen expression, (c) in vitro studies examining differential gene expression in CRISPR-Cac9 derived FGFR3 knockout compared with FGFR active tumor cells, and (d) by an analysis of the immune microenvironment and FGFR3 expression in human bladder specimens using RNA in situ hybridization and multichannel immunofluorescence. The predictive capacity of these param- eters will be assessed in relation to outcomes for patients treated with anti-PD-1/L1 immunotherapy. Dr. Sweis is a physician-scientist from the University of Chicago and is the principle investigator on this study. He has devised a career development plan to obtain training in advanced tumor immunology and laboratory mouse modeling in order to facilitate his development as an independent investigator. He has developed a mentoring committee with broad expertise that is led by Dr. Thomas Gajewski, an internationally renowned expert in cancer immunology. Dr. Sweis has dedicated his efforts to the investigation of immunotherapy resistance mechanisms to improve outcomes for patients.

 
385
Projects
USD 185.3 M
Aggregated funding amount
USD 592 K
Average funding amount
Project list item
Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer

National Cancer Institute to NINA BHARDWAJ, MATTHEW GALSKY, JUN ZHU

USD 703,400
2020 - 2025
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CD40 agonism for the treatment of bladder cancer

National Cancer Institute to CHRISTOPHER STUART GARRIS

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Effect of APOBEC3 on Bladder Cancer Biology and Response to Immunotherapy

National Cancer Institute to ANDREW TRUONG

USD 45,016
2020 - 2023
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A new bladder cancer model based on tissue reprogramming and gene targeting

National Cancer Institute to FLAMINIA TALOS, DAIFENG WANG

USD 203,843
2020 - 2021
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Roles of epigenetic regulators in bladder cancer progression

University of California - Cancer Research Coordinating Committee to Zhu Wang

USD 74,960
2020 - 2020
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Engineering Smart Solutions for Disorders of the Bladder Urothelium

Engineering and Physical Sciences Research Council

 
2019 - 2023
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Bladder cancer chemotherapy potentiation with a multiprong arachidonic acid pathway modulator

National Cancer Institute to PAUL THOMAS HENDERSON

USD 300,000
2019 - 2020
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[The association between SORL1 and advanced bladder cancer] - Original in Japanese

Japan Society for the Promotion of Science to Takanobu UTSUMI

USD 26,335
2019 - 2021
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Developing a SMART scaffold for bladder augmentation

National Institute of Biomedical Imaging and Bioengineering to GUILLERMO ANTONIO AMEER, ARUN SHARMA, JOHN ROGERS

USD 709,004
2019 - 2023
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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
Transdifferentiation of fibroblasts to urothelial progenitors for definitive urothelial replacement therapy in non-muscle invasive bladder cancer

Bladder Cancer Advocacy Network to Philip A Beachy, Kris Butalid Prado

USD 300,000
2019 - 2021
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Recombinant CCL2 as a novel treatment strategy for bladder cancer

Bladder Cancer Advocacy Network to Neelam Mukherjee, Robert Scott Svatek

USD 50,000
2019 - 2020
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Targeting FGF in Bladder cancer after Neoadjuvant Immunotherapy and Surgery

American Association For Cancer Research to Joshua James Meeks

USD 25,000
2019 - 2020
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Identifying Immunological Basis for Bladder Cancer Sex Bias

Canadian Institutes of Health Research to Hyunwoo Kwon, Zihai Li

USD 26,376
2019 - 2022
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[Cancer immunotherapy targeting treatment-resistant urothelilal cancer stem cells] - Original in Japanese

Japan Society for the Promotion of Science to 愛子 村井

USD 38,275
2019 - 2021
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Combatting Bladder Cancer by Inducing Epithelial Turnover

National Cancer Institute to SOMAN N ABRAHAM

USD 372,404
2019 - 2021
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Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

National Cancer Institute to BYRON H LEE

USD 486,410
2019 - 2024
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Phase 1/2 Study of Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder - (ADAPT-BLADDER)

National Cancer Institute to NOAH M HAHN

USD 1,313,632
2019 - 2024
Project list item
Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

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USD 821,670
2019 - 2024
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