Our research goal is to develop a new, robust therapeutic agent that seeks and destroys human neuroblastoma. Neuroblastoma is the most common cancer in infancy and children. High-risk neuroblastomas are difficult to cure even with the most aggressive of combination or multi-modal therapies. Our preliminary studies suggest the feasibility of using new protelipid nanovesicles to target and treat neuroblastomas with minimal side effects. The nanovesicle is consisted of the small fusogenic lysosomal protein saposin C (SapC) and the phospholipid dioleoylphosphatidylserine (DOPS). This stably formed SapC-DOPS nanovesicle has preferential affinity for phosphatidylserine (PS) exposed on the surface of cancer cells and neovessels. We have shown that the nanovesicles have high propensity to accumulate in neuroblastoma tumors, and induces apoptosis in the cancer cells. Upon repeated SapC-DOPS injection in neuroblastoma-bearing animals, we observed a significantly inhibitory effect on tumor growth by inducing apoptotic cancer cell death via acid sphingomyelinase-derived ceramide-mediated signaling pathways. The objective in this proposal is to determine SapC-DOPS nanovesicles for their application in treating neuroblastomas.
The specific aims are to (1) determine the relationship of cell surface PS levels of human neuroblastoma cells and the targeting and cytotoxic responses to SapC-DOPS nanovesicles, (2) develop a SapC-DOPS sensitization agent that specifically promotes the PS exposure on the surface of human neuroblastoma, and (3) delineate the molecular mechanism underlying SapC-DOPS induced apoptotic cell death of human neuroblastoma via the ceramide-mediated mitochondria-centric signaling pathway. This research is innovative because SapC-DOPS nanovesicles offer a unique approach for seeking and treating neuroblastomas, as well as other tumors with cell surface exposed PS. The successfully completion of the proposed research will have a major impact on the field of cancer clinical research, since it provides a safe and broad clinical approach for cancer therapy.

Public Health Relevance

Neuroblastoma is an extracranial solid cancer that most commonly occurs in infancy and childhood. Current treatment methods for high risk neuroblastomas, consisting of surgery, radiation, and multi-modal chemotherapy, have not been effective in significantly improve survival rate. There is an urgent need for efficacious treatments. We are creating a new therapeutic agent for treating neuroblastomas. Our novel approach is to use protein-lipid nanovesicles that can preferentially seek cancer and selectively destroy tumor cells without damaging normal cells. We are investigating the cancer-selective targeting and killing mechanism of the nanovesicles using human neuroblastoma cells and animal models. Success in the proposed research studies will enable us to test the product in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA158372-04
Application #
8704285
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2011-09-27
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$315,542
Indirect Cost
$108,178
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Winter, Patrick M; Pearce, John; Chu, Zhengtao et al. (2015) Imaging of brain tumors with paramagnetic vesicles targeted to phosphatidylserine. J Magn Reson Imaging 41:1079-87
Unruh, Dusten; Turner, Kevin; Srinivasan, Ramprasad et al. (2014) Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma. Int J Cancer 134:9-20
Chu, Zhengtao; LaSance, Kathleen; Blanco, Victor et al. (2014) In vivo optical imaging of brain tumors and arthritis using fluorescent SapC-DOPS nanovesicles. J Vis Exp :
Olowokure, Olugbenga; Qi, Xiaoyang (2014) Pancreatic cancer: current standards, working towards a new therapeutic approach. Expert Rev Anticancer Ther 14:495-7
Wojton, Jeffrey; Chu, Zhengtao; Mathsyaraja, Haritha et al. (2013) Systemic delivery of SapC-DOPS has antiangiogenic and antitumor effects against glioblastoma. Mol Ther 21:1517-25