We are proposing to develop a new treatment for targeting and eliminating glioblastoma multiforme (GBM, high grade glioma), a deadly and invasive brain tumor with no effective treatment. Of the 12,000 patients expected to be diagnosed with GBM this year, most will succumb within the first year. GBM tumors have proven to be resistant to existing anti-cancer therapies. Complete surgical ablation is nearly impossible because invasive cells remain hidden in the brain. The tumor returns rapidly. There is an urgent demand and a growing market for an efficacious anti-glioma drug. To address this need, we are planning to determine the feasibility of using novel proteolipid nanovesicles to target and destroy glioma tumor cells. Composed of the small lysosomal protein saposin C (SapC, 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles have unusually high affinity for phosphatidylserine-enriched membrane surfaces which are common in many types of tumor cells. To check whether the nanovesicles could be used for targeting and attacking tumor cells, we conducted preliminary in vitro and in vivo assays and discovered that, indeed, the nanovesicles have high propensity to accumulate in tumors, and very importantly, in gliomas. Upon repeated SapC-DOPS injection in tumor-bearing mice, we noticed a reduction in tumor size and improved survival. These intriguing observations prompted us to explore the use of SapC-DOPS as a potentially therapeutic drug for treating aggressive brain tumors. In Phase I of this proposal, our specific aims are: (1) Confirm that Saposin C (SapC) is necessary for delivery of nanovesicles to intracranial gliomas and evaluate the biodistribution of the nanovesicles in vivo, (2) Using a bioluminescent glioma xenograft model, determine the dose-dependent elimination of tumor cells by SapC-DOPS nanovesicles, and (3) Evaluate the anti-tumor activity of SapC-DOPS nanovesicles against a second type of glioma with aggressive and invasive growth properties. Tissues from treated mice will be analyzed to confirm that the nanovesicles are relatively nontoxic at useful doses. Neurological evaluation will be performed, monitoring for evidence of toxicity. Upon the completion of these studies, we expect to have compelling evidence to support further development of SapC-DOPS nanovesicles as a first-line anti-glioma therapeutic. In Phase II, detailed optimization, efficacy, distribution, pharmacokinetics, scale-up, and safety studies will be conducted, while in Phase III, the emphasis will be on IND-enabling studies to move the product toward clinical testing. This research is innovative because SapC-DOPS nanovesicles offer a unique approach for imaging and eliminating hidden brain tumors. Eventually, we expect to adapt our technology for targeting different types of tumors and for developing tumor-targeted diagnostics.
Public Health Relevance: We are developing a new treatment for glioblastoma multiforme, a deadly form of brain tumor that kills over 90% of afflicted patients. Current treatment methods, consisting of surgery, radiation, and chemotherapy, have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in the proposed animal models will enable us to test the product in humans.
Public Health Relevance: PROJECT NARRATIVE We are developing a new treatment for glioblastoma multiforme, a deadly form of brain tumor that kills over 90% of afflicted patients. Current treatment methods, consisting of surgery, radiation, and chemotherapy, have not been effective in significantly reducing morbidity. Our strategy involves using new proteolipid nanovesicles that can penetrate the tumors and selectively destroy malignant cells without harming normal cells. Success in the proposed animal models will enable us to test the product in humans. 3
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