Despite advances in surgery, chemotherapy, and radiation therapy, the average life span of a patient with glioblastoma multiforme (GBM) is about 15-months from time of diagnosis. Integrins are heterodimeric receptors found on the surface of GBM cells and angiogenic vasculature; they facilitate invasion into adjacent tissue. Normal brain tissue does not display activated integrins. Therapy for GBM based on integrin antagonism is most attractive, targeting both the neovasculature and the tumor itself. Our approach in this Phase I STTR is based on peptides known as disintegrins. Disintegrins bind with high affinity to a subset of human integrins involved in GBM and angiogenic endothelial cell invasion to inhibit tumor dissemination. The disintegrin we are studying, vicrostatin (VCN), is a recombinant single-chain peptide with all 10 cysteine residues involved in disulfide bond formation. We have shown that VCN has potent antitumor/antiangiogenic activity in breast, ovarian and prostate cancer. Advantages of VCN as GBM therapy: ability of VCN to disrupt the locomotor apparatus of the cell (actin cytoskeleton) and dramatically inhibit invasiveness of both GBM cells and angiogenic vasculature; minimal off-target effects due to lack of activated integrin expression in normal brain tissue; stable peptide enabling better penetration through the blood-tumor barrier; an exclusive recombinant production method that is robust, low cost and easily scalable; and stability of VCN to iodination with only a single tyrosine residue (Y51 in the amino acid sequence) iodinated. Since VCN is able to target integrins expressed on the luminal surface of GBM endothelium, 131I-VCN may be administered either intratumorally (i.t.) or intravenously (i.v.). Brachytherapy for malignant gliomas has been traditionally performed via invasive radioactive probes placed intracranially into the glioma. The use of 131I-VCN to selectively target integrins overexpressed on the angiogenic tumor endothelial cells and glioma cells will enable a novel non-invasive i.v. delivery modality with uniform distribution throughout the tumor. We propose two Specific Aims: In Aim 1 we will perform a dose-response study using 131I-VCN, delivered i.v. or i.t. to GBM in mouse models. 131I-VCN will deliver a dual effect by: (i) VCN integrin antagonistic activity, which blocks invasion of GBM and associated endothelial cells, and (ii) the brachytherapy effect from 131I. 131I- VCN binds specifically to GBM cells and associated angiogenic endothelial cells, but not to normal brain tissue, limiting the brachytherapy affect to the tumor. We will examine toxicity to normal brain, and the dose response on GBM progression. In Aim 2 we will examine combination of 131I-VCN (at optimal VCN and 131I dose) with antiangiogenic therapy or chemotherapy, and compare efficacy of the individual agents to their combination using GBM cells stereotactically implanted, as in Aim 1, with survival and tumor size as end points. We have assembled a unique team of experts including: a neurosurgeon, disintegrin/integrin specialist, molecular biologist, radiation oncologist, medical physicist, animal model specialist and biostatistician.
Public Health Relevance Statement: Public Health Relevance: Glioblastoma multiforme (GBM) is a devastating brain cancer affecting males and females young and old. Despite advances in surgery, chemotherapy, and radiation therapy, the average life span of a patient with GBM is ~15 months from time of diagnosis. It is critical, therefore, that new treatment options be made available for patients wit this devastating disease. This application will demonstrate that 131I-vicrostatin (VCN), a disintegrin that targets integrins involved in both GBM invasion and angiogenesis, represents an effective and novel therapy for GBM. Further, VCN, as an integrin antagonist, can be used with other anticancer agents to provide a unique form of combination therapy with additional therapeutic benefit. We propose two Specific Aims. In Aim #1 we will complete a dose response study using both intravenous and intratumoral delivery of 131I-VCN to establish the effective dose that does not cause concomitant side effects in normal brain tissue. In Aim #2 we will examine combination of 131I-VCN with a chemotherapeutic agent or with another antiangiogenic agent and compare efficacy of the individual agents to their combination. We will use orthotopic mouse GBM models to demonstrate that 131I-VCN has dual activities of an anti-invasive and a brachytherapy agent.
Project Terms: Actins; Adverse effects; Affect; Affinity; Amino Acid Sequence; Amino Acids; angiogenesis; Angiogenesis Inhibitors; Animal Model; Antineoplastic Agents; Apoptotic; Avastin; base; bevacizumab; Binding (Molecular Function); Blood; Blood Vessels; Bone Marrow; Brachytherapy; Brain; brain tissue; cancer cell; Cell Surface Proteins; Cells; chemotherapeutic agent; chemotherapy; Clinic; Clinical Trials; Combined Modality Therapy; comparative efficacy; contortrostatin; cost; Cysteine; Cytoskeleton; Development; Diagnosis; Dialysis procedure; Disease; Disintegrins; disulfide bond; Dose; Endothelial Cells; Endothelium; Exhibits; Extracellular Matrix; Family; Female; Fluorescence Polarization; Glioblastoma; Glioma; Harvest; Heart; Human; Implant; implantation; Individual; inhibitor/antagonist; Integrin Binding; Integrins; Intravenous; Invaded; Iodination reaction; irinotecan; Kidney; Link; Liver; Longevity; Luciferases; Lung; male; malignant breast neoplasm; Malignant Glioma; Malignant neoplasm of brain; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Medical; Methods; migration; Modality; Modeling; Molecular; Monitor; mouse model; Mus; neoplastic cell; neovasculature; Neurosurgeon; novel; Nude Mice; Nutrient; Operative Surgical Procedures; Oral; Organ Harvestings; overexpression; Oxygen; Patients; Penetration; Peptides; Phase; Phosphate Buffer; Platelet Aggregation Inhibition; Production; public health relevance; Pump; Radiation; Radiation Oncologist; Radiation therapy; Radioactive; Radioactivity; receptor; Recombinants; Recurrence; Repeat Surgery; response; Saline; Small Business Technology Transfer Research; Snake Venoms; Specialist; Surface; Technology; temozolomide; Therapeutic; Thyroid Gland; Time; Tissues; Topoisomerase Inhibitors; Toxic effect; tumor; tumor growth; Tumor Tissue; Tyrosine; U251; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Wit
