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John Zhang, PhD

Associate Professor

Medical University of South Carolina

Medicine

http://academicdepartments.musc.edu/facultydirectory/Zhang-Xian

A novel approach for treating lupus by inhibiting Fli1 transcription factor

Lupus patients with active disease produce higher-than-normal amounts of the protein Fli-1 in their immune cells. The more of the protein they make, the worse their symptoms are. He has found that the drug topotecan, a therapy for ovarian cancer and other types of cancers, curbs production of Fli-1 and reduces the signs of inflammation in cells. He will test whether the drug has beneficial effects in lupus-prone mice. His results will help demonstrate whether the drug has potential as a lupus treatment in patients

 

What this study means to people with lupus

 

Dr. Zhang’s team is confirming their initial findings and now testing in human cells whether the chemotherapy topotecan could offer an effective treatment to reduce inflammation in lupus. Topotecan blocks Fli-1, a protein Dr. Zhang and his team have determined worsens lupus symptoms.

We and others have demonstrated that expression of Fli-1 transcription factor affects lupus disease development. Lupus patients with active disease had elevated expression of Fli-1 in blood lymphocytes compared to healthy controls and overall Fli-1 expression paralleled disease activity measures. Transgenic mice with overexpression of Fli-1 in normal strain developed lupus disease. MRL/lpr and NZM2410 mice, murine model of lupus, with genetically reduced expression of Fli-1 had profound improved renal disease and survival. We have found that Fli-1 is a critical regulator in controlling expression of inflammatory mediators in endothelial cells and immune cells. Inhibiting expression of Fli-1 in endothelial cells, monocytes resulted in significantly reduced production of inflammatory mediators. Chemotherapy drug camptothecin can inhibits expression of Fli-1 at low concentration without toxicity, cells treated with camptothecin produce significantly reduced inflammatory mediators. Thus here we will test if topotecan (water soluble analogue of camptothecin), a Fli-1 inhibitor, has therapeutic effects in murine models of lupus and if the human T cells, B cells, macrophages produce significantly decreased inflammatory mediators following the treatment with Topotecan. Since Topotecan is an FDA-approved clinical drug, results from these experiments could be rapidly translated for the treatment of human lupus patients.

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