Targeting gene product in tumors is very important for systemic gene delivery because only a portion of genes are successfully delivered into tumors by using the most successful systemic tumor-targeted gene delivery technology. More importantly, some gene products such as IL-12 are more effective when co-localized with tumors, compared to staying in blood or other organs One simple approach to targeting gene product into tumors is to generate and use fusion genes encoding IL-12 and tumor-targeted mini-peptide. Unexpectedly, we found that none of the known tumor-targeted peptides boost IL-12-induced anti-tumor efficacy. In the current grant period, however, we discovered the novel peptide VNTANST, which boosts accumulation of IL-12 protein into tumors when a fusion gene encoding IL-12-VNTANST, was administered into muscles distant from the tumors. Using a gene therapy approach for DNA delivery and using a fusion gene product IL-12-VNTANST for tumor-targeting (tumor-targeted IL-12 gene therapy has shown great potential in inhibiting tumors in multiple tumor models. We also revealed that this tumor-targeting IL-12 (IL-12-VNTANST) binds to vimentin, a protein known as an intracellular protein and increased in metastatic tumors. An intriguing question is how the extracellular IL-12-VNTANST binds to an intracellular protein? Significantly, our preliminary study showed that vimentin is found on the cell membrane of malignant epithelial cells. Our objective in this renewal application is to determine whether membrane vimentin localization is increased in some of the metastatic tumor cells and thus has a significant role in binding to IL-12-VNTANST and boosting IL-12-anti-tumor efficacy. We will also examine how to effectively using this targeted IL-12 gene therapy for treating membrane positive metastatic tumors in various organs using tumor-targeted IL-12 gene therapy. We hypothesize that tumor-targeted IL-12- VNTANST gene therapy has a great potential for treating membrane vimentin positive metastatic tumors. The proposed study is innovative because it may definitively confirm that the membrane vimentin localization plays a key role for tumor metastasis and for boosting the proposed targeted IL-12 gene therapy. Confirmation of membrane vimentin dependence would also allow us selecting proper tumor-bearing patient in the future to perform this therapy, which is so called personalized immune therapy, an important direction of novel therapeutics and a long term of goal of our effort.

Public Health Relevance

Tumor recurrence and metastasis after primary therapy are the major causes of death in cancer patients. Metastatic tumor-targeted therapy is lacking. In this application, we will determine how to effectively use this targeted immune therapy for treating metastatic tumors in different organs with a goal of moving this therapy in human clinics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120895-07
Application #
8463469
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Yovandich, Jason L
Project Start
2006-08-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$273,722
Indirect Cost
$100,480
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Satelli, Arun; Mitra, Abhisek; Brownlee, Zachary et al. (2015) Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin Cancer Res 21:899-906
Satelli, Arun; Mitra, Abhisek; Cutrera, Jeffry J et al. (2014) Universal marker and detection tool for human sarcoma circulating tumor cells. Cancer Res 74:1645-50
Wang, Xiaohong; Li, Shulin (2014) Protein mislocalization: mechanisms, functions and clinical applications in cancer. Biochim Biophys Acta 1846:13-25
Mitra, Abhisek; Satelli, Arun; Yan, Jun et al. (2014) IL-30 (IL27p28) attenuates liver fibrosis through inducing NKG2D-rae1 interaction between NKT and activated hepatic stellate cells in mice. Hepatology 60:2027-39
Dibra, Denada; Mishra, Lopa; Li, Shulin (2014) Molecular mechanisms of oncogene-induced inflammation and inflammation-sustained oncogene activation in gastrointestinal tumors: an under-appreciated symbiotic relationship. Biochim Biophys Acta 1846:152-60
Yan, Jun; Li, Song; Li, Shulin (2014) The role of the liver in sepsis. Int Rev Immunol 33:498-510
Mitra, Abhisek; Mishra, Lopa; Li, Shulin (2013) Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol 31:347-54
Cutrera, Jeffry; Johnson, Blake; Ellis, Lee et al. (2013) Intraosseous inoculation of tumor cells into bone marrow promotes distant metastatic tumor development: A novel tool for mechanistic and therapeutic studies. Cancer Lett 329:68-73
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
Reed, S D; Li, S (2011) Pre-clinical toxicity assessment of tumor-targeted interleukin-12 low-intensity electrogenetherapy. Cancer Gene Ther 18:265-74

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