ACTIVATION OF ANTITUMORIGENIC STAT3BETA IN BREAST CANCER BY SPLICING REDIRECTION

Project Details

Description

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).
StatusFinished
Effective start/end date7/1/127/31/17

Funding

  • Congressionally Directed Medical Research Programs (CDMRP)

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