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Project

Novel therapeutic targets in invasive bladder cancer

Funder: American Association For Cancer Research

Funding period
USD 45 K
Funding amount
Abstract
Background: Muscle-invasive bladder cancer is one of the major clinical challenges with high mortality resulting in the proximal cause of ~14,000 deaths in the U.S. Recently we established a novel mouse model of invasive bladder cancer based on the combinatorial deletion of p53 and Pten in bladder epithelium using an adenovirus expressing Cre recombinase (Adeno-Cre) delivered to the bladder lumen of p53flox/flox;Ptenflox/flox mouse (Puzio-Kuter Gene Dev 2009). We found marked upregulation of tumor suppressor ARF in tumor tissue compared to normal epithelium in our mouse model.Hypothesis: We hypothesize that ARF has a previously unknown function in promoting bladder tumorigenesis in the context of p53- and Pten-deficiency, which can be a potent therapeutic target in bladder cancer treatment.Rationale: Invasive bladder cancer in our mouse model shows histological and genetic features highly similar to those of aggressive human invasive bladder cancer. Additionally, we have demonstrated the usefulness of our mouse model in preclinical study (Seager Cancer Prev Res 2009). In terms of functional significance of ARF, we found that tumors induced in Arfflox/flox; p53flox/flox; Ptenflox/flox triple flox (TKO) mice grew more slowly and allowed longer survivals than those induced in p53flox/flox;Ptenflox/flox double flox (DKO) mice. Our preliminary data showed that some tumor suppressors including TSC2 and p16 were upregulated in TKO tumors in correlation with decreased proliferation status as assessed by Ki67 expression.Specific aims: We aim (1) to elucidate molecular pathways through which ARF suppresses TSC2 an p16 expression and promotes tumorigenesis, and (2) to investigate clinical significance of role of ARF in human bladder cancer.Study design: We will investigate key regulators of tumor-promoting pathways involving ARF by master regulator analysis in which differential gene expression profiles of TKO and DKO mouse tumors are compared with a large-scale human bladder gene regulation maps (interactome). Simultaneously, we will investigate the transcriptional activity of specific transcription factors that potentially bind to the TSC2 promoter region preserved beyond species. Then we will validate the hypothetical pathways functionally using human bladder cancer cells. Clinical significance of the activation of the molecular pathways will be interrogated by high throughput immunohistochemical analysis on tissue microarray. Finally we will utilize our mouse model to examine whether the molecules involved in the tumor-promoting pathway can be a predictive factor or therapeutic target in the treatment of invasive bladder cancer.Relevance to cancer: Since previously known p53-independent function of ARF is mostly tumor-suppressive, novel tumor-promoting functions of ARF would have a significant impact on the entire field of cancer research. Additionally, our research will provide promising treatment strategies for bladder cancer treatment.

 
359
Projects
USD 185.6 M
Aggregated funding amount
USD 631 K
Average funding amount
Project list item
Intravesical delivery of an Fc-enhanced CD40 agonist antibody for the treatment of bladder cancer

Bladder Cancer Advocacy Network to Jeffrey Ravetch, David Knorr

USD 300,000
2020 - 2022
Project list item
Epigenetic regulators of subtype plasticity in bladder cancer

Bladder Cancer Advocacy Network to John Robert Christin

USD 1,700
2020 - 2020
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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
2020 - 2021
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Defining NRF2 induced tumor invasion in bladder cancer

Bladder Cancer Advocacy Network to Yuki Kita, William Youngkwan Kim, Bernard Weissman

USD 50,000
2020 - 2021
Project list item
Alpha1H: A Unique Bladder Cancer Therapeutic, Acting with Great Precision

European Commission

USD 2,452,885
2020 - 2022
Project list item
Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer

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

USD 703,400
2020 - 2025
Project list item
Implication of neutrophil extracellular traps in the efficacy of bladder-sparing therapy in muscle invasive bladder cancer

Canadian Institutes of Health Research to Wassim Kassouf, Ciriaco A. Piccirillo, Jonathan David Spicer

USD 138,878
2020 - 2025
Project list item
Chimeric RNAs and their implication in lymphatic metastasis of bladder cancer

National Cancer Institute to HUI LI

USD 205,913
2020 - 2025
Project list item
CD40 agonism for the treatment of bladder cancer

National Cancer Institute to CHRISTOPHER STUART GARRIS

USD 64,554
2020 - 2023
Project list item
Effect of APOBEC3 on Bladder Cancer Biology and Response to Immunotherapy

National Cancer Institute to ANDREW TRUONG

USD 45,016
2020 - 2023
Project list item
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
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
Chemotherapy plus PD-1 blockade as bladder-sparing treatment for muscle-invasive bladder cancer

V Foundation for Cancer Research to Matthew D Galsky

USD 600,000
2019 - 2022
Project list item
Unravelling Mechanisms of Resistance to Checkpoint Inhibition in Canine Urothelial Carcinoma

V Foundation for Cancer Research to Nicola J. Mason

USD 500,000
2019 - 2021
Project list item
Engineering Smart Solutions for Disorders of the Bladder Urothelium

Engineering and Physical Sciences Research Council

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

National Cancer Institute to PAUL THOMAS HENDERSON

USD 300,000
2019 - 2020
Project list item
[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
Project list item
Developing a SMART scaffold for bladder augmentation

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

USD 1,399,891
2019 - 2023
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