SapC-DOPS Nanovesicles for Treating Glioblastoma Multiforme

DESCRIPTION (provided by applicant): Our goal is to develop a new molecular entity with a novel mechanism of action 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 a year. There is an urgent demand for an efficacious anti-glioma drug. We are developing a new class of therapeutic proteolipid nanovesicle that can target anddestroy glioma tumors. Composed of the small lysosomal sphingolipid activator protein saposin C (SapC, 80 aa) and the phospholipid dioleoylphosphatidylserine (DOPS); the stable 200 nm SapC-DOPS nanovesicles (clinical formulation is called BXQ-350) have unusually high affinity for phosphatidylserine-enriched membrane surfaces that occur widely in many types of tumor cells and tumor neovasculature. Consistent with sphingolipid activator function, BXQ-350 appear to selectively induce tumor cells to undergo ceramide-mediated cell death, apparently sparing non-tumor cells. In Phase I of this proposal, we demonstrated the feasibility of using SapC-DOPS to target and kill intracranial gliomas. Intravenous administration of SapC-DOPS in mice with orthotopically implanted gliomas resulted in dose-dependent improvement in survival. In Phase II, a GMP compliant formulation of SapC-DOPS (i.e., BXQ-350) was developed, and potency was confirmed in additional orthotopic preclinical GBM models. IND-enabling studies are in progress. Pharmacokinetics and toxicity studies thus far indicate favorable distribution and safety profiles in rodent and non-rodent studies. In this three-year Phase IIB proposal, the key objectives are to file the IND for BXQ-350, complete a Phase 1 clinical trial, and prepare for Phase 2. Recognizing that gliomas are highly heterogeneous, another objective is to identify and link biochemical factors (e.g., cell surface PS levels; genetic markers) to the degree of BXQ-350 tumoricidal activity. Understanding of these factors will improve dosing strategies and reduce the risk of variable therapeutic response. Specific Aims are: (1) Scale- up GMP production of BXQ-350; (2) File the IND and complete the Phase 1 clinical trial; and (3) Correlate susceptibility to killing by BXQ-350 with molecular and cellular characteristics of glioma cell lins (from a tumor bank). BXQ-350 offers an innovative and potentially powerful approach for slowing tumor growth and eliminating deep-seated brain tumors. Ultimately, we willprogress this technology for treating other tumors and for developing tumor-targeted imaging diagnostics. PUBLIC HEALTH RELEVANCE 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 clinical trials will enable us to offer an effective new strategy to treat patients with aggressive brain tumors.