Great effort has been made in developing tumor-targeted gene delivery, but no attention has been given to targeting the therapeutic gene products that are transcribed and translated from genes transfected in normal tissues into tumors. 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. Targeting gene product in tumors is also important for intratumoral gene delivery because the most commonly used therapeutic genes like TRAIL yield soluble proteins that are secreted into the blood circulation and are harmful to normal cells. Moreover, some gene products such as IL-12 are more effective when co-localized with tumors, compared to systemic localization (Li, S., JNCI, 2002;Li, S., Mol Therapy, 2005). In this application, the applicant will select the effective tumor vessel-targeted peptides to target or anchor the therapeutic gene product transcribed and translated from the injected gene into tumors. Specifically, tumor vessel- anchored IL-12 gene encoding the selected tumor vessel-anchored mini-peptide and IL-12 will be generated and will be administered into tumors via electric pulses to achieve the tumor-targeted gene delivery and the tumor-targeted gene-product auto-delivery. The hypothesis is that the increased IL-12 accumulation in tumor and reduction of IL-12 circulation in serum by using tumor vessel-anchored IL-12 electrogenetherapy will greatly reduce systemic toxicity and enhance tumor eradication. To test this hypothesis, we will 1) select the most effective peptides for anchoring gene product that are transcribed and translated from the injected gene into tumors using our high throughput in vivo screening system;2) Determine the therapeutic efficacy of tumor vessel-anchoring IL-12 electrogenetherapy for treating tumors in immunocompetent tumor-bearing mice and spontaneous tumor bearing felines;and 3) test a novel mechanism by which IL-12 inhibits tumor angiogenesis and by shich tumor vessel-anchored IL-12 enhances the inhibition of tumor angiogenesis. The experiments that we propose have a high probality of success because we have an excellent model system in place, the access to spontaneous tumor- bearing large animals, and all the resources necessary to complete the task.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA120895-04
Application #
7841898
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Yovandich, Jason L
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$300,200
Indirect Cost
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
Hu, Jiemiao; Bernatchez, Chantale; Zhang, Liangfang et al. (2017) Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8+ T Cells and Histone Acetyltransferases. Cancer Immunol Res 5:300-311
Satelli, Arun; Batth, Izhar; Brownlee, Zachary et al. (2017) EMT circulating tumor cells detected by cell-surface vimentin are associated with prostate cancer progression. Oncotarget 8:49329-49337
Gu, Shoujun; Nguyen, Bao-Ngoc; Rao, Shuyun et al. (2017) Alcohol, stem cells and cancer. Genes Cancer 8:695-700
Batth, I S; Mitra, A; Manier, S et al. (2017) Circulating tumor markers: harmonizing the yin and yang of CTCs and ctDNA for precision medicine. Ann Oncol 28:468-477
Li, Heming; Meng, Qing H; Noh, Hyangsoon et al. (2017) Detection of circulating tumor cells from cryopreserved human sarcoma peripheral blood mononuclear cells. Cancer Lett 403:216-223
Satelli, Arun; Batth, Izhar Singh; Brownlee, Zachary et al. (2016) Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci Rep 6:28910
Noh, Hyangsoon; Yan, Jun; Hong, Sungguan et al. (2016) Discovery of cell surface vimentin targeting mAb for direct disruption of GBM tumor initiating cells. Oncotarget 7:72021-72032
Satelli, Arun; Hu, Jiemiao; Xia, Xueqing et al. (2016) Potential Function of Exogenous Vimentin on the Activation of Wnt Signaling Pathway in Cancer Cells. J Cancer 7:1824-1832
Dibra, Denada; Mitra, Abhisek; Newman, Melisa et al. (2016) Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 In Vivo. Clin Cancer Res 22:3876-83
Mitra, Abhisek; Satelli, Arun; Xia, Xueqing et al. (2015) Cell-surface Vimentin: A mislocalized protein for isolating csVimentin(+) CD133(-) novel stem-like hepatocellular carcinoma cells expressing EMT markers. Int J Cancer 137:491-6

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