To realize the promise of gene therapy as a treatment modality for cancer, we must develop simplified but effective gene delivery approaches and understand how therapeutic proteins act to kill tumors. Our proposal directly addresses both of these critical elements. We have pioneered the use of muscle-based electroporation as a novel and inexpensive approach for simplified and effective gene delivery and have demonstrated that injection of the IL-12 gene to muscle accompanied by electroporation substantially enhances the level of IL-12 expression and its systemic antitumor efficacy, compared with injection without electroporation, leading to 20% eradication of tumors located distant to the gene injection site. We hypothesize that delivery of IL-12 DNA via intramuscular electroporation, in synergy with a novel muscle-specific expression system, will eradicate or inhibit remote squamous cell carcinoma (SCC) by upregulation of antitumor genes. Our long-term goal is to develop a simple and effective strategy for eradicating inaccessible small-load metastatic SCC or residual microscopic SCC after surgery. We will use a tumor model of SCC, known as SCCVII, which allows the generation of both subcutaneous and metastatic tumors in a syngeneic murine host (C3H/HeJ) to explore the following Specific Aims.
Aim 1 : Determine the optimal delivery and expression system for electroporation to achieve therapeutic levels of IL-12 in vivo, and assess the systemic toxicity of gene therapy in comparison to protein therapy.
Aim 2 : Determine the role of Stat 1 and primary immune cells in inhibition of tumor growth elicited by IL-12. This work holds enormous potential for progress in eradicating SCC, particularly in those clinical situations where small-load metastases are inaccessible or in cases where residual microscopic disease persists after surgery. The experiments that we propose have a high probability of success because we have an excellent model system in place, experience in the electroporation gene therapy field, and all the resources necessary to complete the task.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wolpert, Mary K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State University A&M Col Baton Rouge
Veterinary Sciences
Schools of Veterinary Medicine
Baton Rouge
United States
Zip Code
Hu, Jiemiao; Zhu, Shiguo; Xia, Xueqing et al. (2014) CD8+T cell-specific induction of NKG2D receptor by doxorubicin plus interleukin-12 and its contribution to CD8+T cell accumulation in tumors. Mol Cancer 13:34
Wang, Xiaohong; Li, Shulin (2014) Protein mislocalization: mechanisms, functions and clinical applications in cancer. Biochim Biophys Acta 1846:13-25
Dibra, Denada; Li, Shulin (2013) The cell-to-cell coordination between activated T cells and CpG-stimulated macrophages synergistically induce elevated levels of IL-10 via NF-?B1, STAT3, and CD40/CD154. Cell Commun Signal 11:95
Dibra, Denada; Cutrera, Jeffry J; Li, Shulin (2012) Coordination between TLR9 signaling in macrophages and CD3 signaling in T cells induces robust expression of IL-30. J Immunol 188:3709-15
Dibra, Denada; Cutrera, Jeffry; Xia, Xueqing et al. (2012) Interleukin-30: a novel antiinflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. Hepatology 55:1204-14
Cutrera, Jeffry; Dibra, Denada; Xia, Xueqing et al. (2011) Discovery of a linear peptide for improving tumor targeting of gene products and treatment of distal tumors by IL-12 gene therapy. Mol Ther 19:1468-77
Satelli, Arun; Li, Shulin (2011) Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 68:3033-46
Dibra, Denada; Cutrera, Jeffry; Xia, Xueqing et al. (2011) WSX1 expression in tumors induces immune tolerance via suppression of effector immune cells. PLoS One 6:e19072
Reed, S D; Li, S (2011) Pre-clinical toxicity assessment of tumor-targeted interleukin-12 low-intensity electrogenetherapy. Cancer Gene Ther 18:265-74
Flanagan, M; Gimble, J M; Yu, G et al. (2011) Competitive electroporation formulation for cell therapy. Cancer Gene Ther 18:579-86

Showing the most recent 10 out of 25 publications