This glioblastoma therapy stems from an experienced team-based approach to developing therapeutic and imaging agents for the treatment, diagnosis and monitoring of glioblastoma and other aggressive malignancies.
Glioblastoma is the most common primary brain tumor in adults. Tumors are aggressive and infiltrate surrounding brain tissue. Median survival is ~14.5 months post diagnosis- survival has only been extended by ~8 month in 8 decades. High mortality in glioblastoma is attributed to complex pathobiology, including high cellularity, neovascularization, hypoxia/necrosis, immune cell infiltration, and local invasion. Four genomic subtypes of glioblastoma are described which, unfortunately, are not associated with survival or responses to treatment, except for patients with the proneural IDH1 subtype.
Researchers at Wake Forest School of Medicine are developing therapeutic biologics and imaging agents for the diagnosis, monitoring and treatment of glioblastoma.
Multivalent constructs have been created for multi-compartmental glioblastoma therapy which specifically bind to receptors that are overexpressed in glioblastoma but not normal brain tissue. Specifically, Interleukin receptor alpha 2 (IL-13RA2), EphA2, EphA3, EphB2, together, are overexpressed in:
- Core tumor cells
- Tumor infiltrating cells
- Abnormal neovasculature
- Glioma stem-like cells
- Tumor associated mass composed primarily of abnormal myeloid cells
The multivalent constructs target all glioblastoma compartments believed to be involved in tumor progression and/or resistance to therapies. Collectively all patients express these targets thus all patients may be eligible for treatment. The multivalent constructs serve as delivery vectors for catalysts.
Peptides specific to receptors that are overexpressed in glioblastoma have been developed. The peptides cross the blood-brain tumor barrier and strongly bind their respective receptor, e.g. IL-13RA2. The peptides can deliver imaging molecules that can be used to precisely diagnose brain tumors and monitor disease progression/ regression.
Additionally, the peptides may be conjugated to cytotoxic agents to create a theragnostic. Upon binding specifically to brain tumor cells, the peptide-drug conjugates are internalized, killing the tumor cells without affecting normal brain cells.
Clinical trials expertise
Wake Forest Baptist Medical Center is a member of the Adult Brain Tumor Consortium, the goal of which is to develop more effective treatments for malignant brain tumors. More than 50% of brain tumor patients are enrolled into clinical trials at Wake Forest.
- Highly novel and specific
- Treats all patients with glioblastoma
- The first generation of an IL-13 based cytotoxin demonstrated objective clinical efficacy in patients with recurrent glioblastoma
- Debinski is a leading authority on receptor-specific chimeric proteins expressed by tumor cells and immunological aspects of cancer treatment and directs the Brain Tumor Center of Excellence at Wake Forest.
Molecularly targeted anti-glioblastoma drug:
- Treats all patients with glioblastoma – does not require patient pre-screening
- Targets most tumor compartments known to be pathobiologically important
- Highly specific for targets which are overexpressed in most patients with glioblastoma, but not in normal brain
- Performs these functions in one pharmaceutical entity, so it will be suitable for monotherapy and have economic advantage
Stage of Development
- The first generation of an IL-13 based cytotoxin demonstrated objective clinical efficacy in human patients with recurrent glioblastoma
- A cocktail of monovalent constructs is currently being studied in a comparative medicine clinical trial in dogs with spontaneous glioblastoma
- Proof of concept established for multivalent constructs and peptides in human glioblastoma cells
Waldemar Debinski MD, PhD is the lead investigator
Robust patent estate including:
- US 13/264,473, US 13/068,698, PCT/US2014/064983
- Pandya et al. Genes Cancer. 2010 1(5):421-33.
- Debinski et al., PLoS One. 2013 Oct 10.1371/journal.pone.0077719.
- Pandya et al., Neuro Oncol. 2012 14(1):6-18.
Reference #: 06-48, 08-14, 09-34, 09-35, 13-72, 14-66, 14-67