Skip Navigation Links

Use of Internet Explorer for eRA Modules to be Phased Out by July 19, 2021

eRA is phasing out the use of the Internet Explorer browser for eRA modules effective July 19, 2021. For tips and tricks on troubleshooting browser configuration issues, please go here: Tips & Tricks for Fixing Browser Configuration Issues When Using eRA Modules.

Project Information

ACTIVATION OF ANTITUMORIGENIC STAT3BETA IN BREAST CANCER BY SPLICING REDIRECTION

Agency:
CDMRP

DOD/Congressionally Directed Medical Research Programs

Project Number:
BC112622
Contact PI / Project Leader:
CARTEGNI, LUCA
Awardee Organization:
RUTGERS THE STATE UNIV OF NJ NEWARK

Description

Abstract Text:
STAT3 (Signal Transducer and Activator of Transcription 3) is a latent transcription factor with multiple functions in different tissues that is commonly persistently activated in a large fraction of breast cancers, but not in normal cells. Stat3 constitutes an established cancer therapy target because of its pivotal role in oncogenesis: it promotes cell cycle progression and survival, interferes with immunological response, impairs tumor surveillance, and stimulates angiogenesis. An alternative splicing isoform of Stat3, Stat3beta, lacks the transcriptional transactivation domain and can act as a dominant negative over full-length Stat3a by blocking its tumorigenic potential in vitro and in vivo. Furthermore, additional specific functions have also been proposed for Stat3beta, such as potentiating the immunological response or promoting differentiation, that may improve its anti-tumorigenic potential.Our objective is to manipulate the Stat3 splicing switches in vivo to eliminate the oncogenic alpha isoform while simultaneously introducing a beneficial one with dominant-negative characteristics. We have shown that indeed Stat3 splicing can be redirected to quantitatively induce the anti-tumorigenic Stat3beta variant. This switch is associated to breast cancer cell death in vitro and tumor regression in vivo in a breast cancer model system. We want to now expand on these premises to elucidate the mechanism of action of Stat3 beta in vivo and use our understanding of it to further develop antisense compounds that more effectively target aggressive, triple-negative breast cancer by systemic delivery, to move from the current proof of concept to the preclinical studies phase.Specifically we plan: (1) To understand the mechanism that leads to tumor regression in tumors treated with splicing redirection compounds that induce Stat3beta. (2) To develop next-generation Stat3beta splicing re-direction compounds by comparing different chemistries and modes of delivery. (3) To optimize in vivo efficacy of the compounds in multiple triple-negative breast cancer models in mice. We will first explore the in vivo contribution of the previously identified candidate effectors that might mediate the anti-tumor activity of Stat3beta, in particular LEDGF, Cyclin C, STAT1beta, and PCAF. We will then investigate the relative contribution of inducing the splicing shift in the cancer cells only, in the tumor environment, or in both by using compounds targeted to human or mouse cells or both. In parallel, we will compare morpholino chemistry to 2'MOE chemistry and compare different modes of systemic delivery and delivery moieties, and then we will expand our studies to additional in vivo breast cancer models (such as MDA-MB-468 and mammary fat pad-implanted MDA-MB-231).
Project Terms:
Alternative Splicing; angiogenesis; Biological Models; Breast Cancer Cell; Breast Cancer Model; cancer cell; Cell Cycle Progression; Cell Death; Cells; Characteristics; Chemistry; cyclin C; Dominant-Negative Mutation; Environment; Fatty acid glycerol esters; Genetic Transcription; Human; Immune response; Impairment; Implant; improved; In Vitro; in vivo; Length; malignant breast neoplasm; Mammary gland; MDA MB 231; MDA-MB-468; Mediating; Mus; Names; next generation; Normal Cell; Oncogenic; PCAF gene; Phase; preclinical study; Protein Isoforms; RNA Splicing; Role; STAT3 gene; Stat3 protein; targeted cancer therapy; Tissues; Transactivation; transcription factor; triple-negative invasive breast carcinoma; tumor; tumorigenesis; tumorigenic; Tumorigenicity; Variant

Details

Contact PI / Project Leader Information:
Name:  CARTEGNI, LUCA
Other PI Information:
Not Applicable
Awardee Organization:
Name:  RUTGERS THE STATE UNIV OF NJ NEWARK
City:  NEW BRUNSWICK    
Country:  UNITED STATES
Congressional District:
State Code:  NJ
District:  06
Other Information:
Fiscal Year: 2011
Award Notice Date:
DUNS Number: 130029205
Project Start Date: 01-Jul-2012
Budget Start Date:
CFDA Code: 12.420
Project End Date: 31-Jul-2017
Budget End Date:
Agency: ?

Agency: The entity responsible for the administering of a research grant, project, or contract. This may represent a federal department, agency, or sub-agency (institute or center). Details on agencies in Federal RePORTER can be found in the FAQ page.

DOD/Congressionally Directed Medical Research Programs
Project Funding Information for 2011:
Year Agency

Agency: The entity responsible for the administering of a research grant, project, or contract. This may represent a federal department, agency, or sub-agency (institute or center). Details on agencies in Federal RePORTER can be found in the FAQ page.

FY Total Cost
2011 CDMRP

DOD/Congressionally Directed Medical Research Programs

$619,840

Results

i

It is important to recognize, and consider in any interpretation of Federal RePORTER data, that the publication and patent information cannot be associated with any particular year of a research project. The lag between research being conducted and the availability of its results in a publication or patent award varies substantially. For that reason, it's difficult, if not impossible, to associate a publication or patent with any specific year of the project. Likewise, it is not possible to associate a publication or patent with any particular supplement to a research project or a particular subproject of a multi-project grant.

ABOUT FEDERAL REPORTER RESULTS

Publications: i

Click on the column header to sort the results

PubMed = PubMed PubMed Central = PubMed Central Google Scholar = Google Scholar

Patents: i

Click on the column header to sort the results

Similar Projects

Download Adobe Acrobat Reader:Adobe Acrobat VERSION: 3.41.0 Release Notes
Back to Top