STAT3 Inhibitor Effective Against Breast Cancer in Mouse Model

Dysregulation of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies with laboratory mice have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.

STAT3-deficient mouse embryos cannot develop beyond embryonic day seven, when gastrulation initiates. It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells. Constitutive STAT3 activation is associated with various human cancers, and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects.

Investigators at the University of Texas M.D. Anderson Cancer Center (Houston, USA) worked with the C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me), a drug developed by Reata Pharmaceuticals (Irving, TX, USA) and called RTA 402. In vivo studies were done using the mouse 4T1 breast tumor model, which is largely resistant to chemotherapy.

The investigators reported in the May 2007 issue of the journal Cancer Research that treatment of 4T1 cells in vitro with 500 nmol/l RTA 402 for two hours caused inactivation of STAT3, abrogation of invasive growth of 4T1 cells, and lack of apoptosis induction. In vivo studies showed that the drug completely eliminated 4T1 breast cancer growth and lung metastases induced by 4T1 cells in mice when treatment started one day after tumor implantation and significantly inhibited tumor growth when started after five days.

"This paper provides important new data on how RTA 402 works to inhibit the growth and metastasis of cancer,” said Warren Huff, CEO of Reata Pharmaceuticals. "The effects on STAT3 shown in this paper, combined with the drug's proven inhibition of NF-kB [nuclear factor kappa B], indicate that these agents modulate important and inter-related pathways in cancer cells.”


Related Links:
University of Texas M.D. Anderson Cancer Center
Reata Pharmaceuticals