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Principal Investigator: Waldemar Debinski
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $565,969
Funding agency: National Cancer Institute
SUMMARY
Treatment of glioblastoma (GBM) represents an unmet need in medicine. We have been pursuing a
therapeutic approach of delivering potent targeted and specific cytotoxins using continuously evolving
convection-enhanced delivery. Patients with GBM over-express interleukin 13 receptor alpha 2 (IL-13RA2),
EphA2, EphA3 and EphB2 receptors that are present in various pathophysiological compartments of GBM
and all four are expressed in tumor cells of the core of tumor, and in locally-infiltrating tumor cells, while EphA2
is also found in tumor neovasculature. Further, IL-13RA2, EphA2, and EphA3 are associated with, and play
crucial roles in, the pathobiology of glioma stem-like cells. Finally, the EphA3 receptor are found in M2 GBM-
associated macrophages. Thus, collectively, IL-13RA2, EphA2, EphA3 and EphB2 are over-expressed in
principal GBM compartments shown to be involved in tumor progression and/or resistance to therapies. In a
first-of-kind approach, we performed Phase I clinical trial in dogs with spontaneous gliomas, which represents
a faithful model of human disease, using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. We
observed exceptional anti-tumor responses, including several near complete regressions, prolongation of
survival and excellent quality of life in this dose-finding trial, at no toxicity. In addition, we found evidence for
immune system activation during the therapy. Encouraged by these results, we pursued the novel idea of
targeting all four receptors instead of two with one pharmaceutical compound. One of the Eph receptor ligands,
ephrinA5 (eA5), binds EphA2, EphA3 and EphB2 receptors. We have thus generated an agent based on eA5
and IL-13 mutants targeting all four receptors using an IgG1 scaffold (QUAD). In our initial experiments, the
QUAD was conjugated to derivatives of Doxorubicin (Dox) or a derivative of Pseudomonas exotoxin A,
PE38QQR, to generate single pharmaceutical agents and these drug conjugates retained their binding
affinities towards the targeted receptors while demonstrating prominent killing activity on GBM cells. QUAD-
Dox and QUAD-PE38QQR conjugates have already shown prominent, long-lasting anti-tumor effects in dogs
with spontaneous glioma at no toxicity: 60, 88, and 91% of tumor volume regression in the treated dogs,
respectively. Recently, we have conjugated QUAD to DM1, a microtubule-disrupting agent. The QUAD-DM1 is
extremely potent on GBM cells with IC50s in low femtomolar range, ~50x better than the Dox/PE conjugates.
Therefore, we will continue this exciting line of research through Specific Aims as follows. In Specific Aim 1, we
will treat dogs with spontaneous newly diagnosed and recurrent high-grade gliomas with QUAD-DM1. In
Specific Aim 2, we will examine immune responses and the phenotype and genotype of recurring tumors in the
course of QUAD-DM1 therapy. Our approach addresses crucial issues of inter- and intra-tumoral heterogeneity
and evokes an in situ vaccination or so called “tumor inflaming” effect. We envision that this all-out assault,
termed by us “molecular resection”, will result in a more effective management of GBM.
Terms: <14-Hydroxydaunomycin><Abscission><Address><Adriamycine><Affinity><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antitumor Response><Bacterial Toxins><Binding><Biopsy><Blood><Blood Reticuloendothelial System><Blood monocyte><Body Tissues><Brain><Brain Nervous System><Breast Cancer><Cancer Drug><Canine Species><Canis familiaris><Catheters><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Clinical><Combination immunotherapy><Complement><Complement Proteins><Convection><Cytotoxic agent><Cytotoxic drug><Cytotoxin><Development><Developmentally Regulated EPH-Related Tyrosine Kinase><Disease Management><Disorder Management><Dogs><Dogs Mammals><Dose><Dose Limiting><Doxorubicin><Doxorubicina><Drug Monitoring><Drugs><ELK-Related Tyrosine Kinase><EPH Tyrosine Kinase 3><EPH-Like Tyrosine Kinase 1><EPHA3><EPHA3 gene><ETK1><Early-Stage Clinical Trials><Encephalon><Eph Receptor Ligands><EphA2 Protein><EphA2 Receptor><EphA2 Receptor Tyrosine Kinase><EphA2-Tyrosine Kinase><EphA3 Receptor><EphB2 Protein><EphB2 Receptor><EphB2-Tyrosine Kinase><Ephrin Receptor EphA3><Ephrin Receptor EphB2><Ephrin Type-B Receptor 2><Ephrins><Epithelial Cell Kinase Protein><Excision><Extirpation><Genotype><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HEK Gene><HEK protein><HEK4><Heterogeneity><Human Embryo Kinase><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><IL-13><IL-13Ra><IL13><IL13RA1><IL13RA1 gene><IgG1><Immune response><Immune system><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infiltration><Interleukin-13><Interleukin-13 Receptor Alpha><Interleukin-13 Receptor Alpha 1><Intratumoral heterogeneity><Intravenous><Ligand Binding><Long-Term Survivors><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Malignant Breast Neoplasm><Mammary-Derived Tyrosine Kinase 2><Marrow monocyte><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Medicine><Mice><Mice Mammals><Micro-tubule><Microtubules><Modality><Molecular><Molecular Interaction><Molecular Target><Murine><Mus><Mφ><NMR Imaging><NMR Tomography><NR4><Neoplastic Disease Chemotherapeutic Agents><Neuroglial Neoplasm><Neuroglial Tumor><Newly Diagnosed><Nuclear Magnetic Resonance Imaging><Patients><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase 1 Clinical Trials><Phase I Clinical Trials><Phenotype><Play><Primary Brain Neoplasms><Primary Brain Tumors><Primary Neoplasm><Primary Tumor><Property><Pseudomonas ETA><Pseudomonas aeruginosa exotoxin A><Pseudomonas aeruginosa exotoxin A precursor><Pseudomonas aeruginosa toxA protein><Pseudomonas exotoxin A><QOL><Quality of life><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Receptor Protein-Tyrosine Kinase HEK5><Receptor Tyrosine Kinase HEK><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Reflux><Removal><Research><Resistance><Rodent><Rodentia><Rodents Mammals><Role><Staining method><Stains><Surgical Removal><TYRO4><Testing><Therapeutic><Therapeutic Intervention><Time><Tissues><Toxic effect><Toxicities><Tumor Cell><Tumor Volume><Tumor-Specific Treatment Agents><Tumor-associated macrophages><Tumorigenicity><Tyrosine-Protein Kinase Receptor EPH-3><Zeugmatography><anti-cancer drug><anti-tumor effect><anti-tumor response><antitumor effect><assault><cancer microenvironment><cancer progression><canine><cell sorting><combinatorial immunotherapy><complementation><design><designing><developmental><domestic dog><drug distribution><drug/agent><dual immunotherapy><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><glial-derived tumor><glioblastoma multiforme><heterogeneity in tumors><host response><human disease><human model><immune microenvironment><immune system response><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in situ vaccination><interest><intervention therapy><intra-tumoral heterogeneity><intratumor heterogeneity><longterm survivors><malignant breast tumor><model of human><monocyte><mutant><neoplasm progression><neoplasm recurrence><neoplastic cell><neoplastic progression><neovasculature><neuroglia neoplasm><neuroglia tumor><novel><overexpress><overexpression><pharmaceutical><phase I protocol><progenitor-like cell><receptor><resection><resistance to therapy><resistant><resistant to therapy><response><scaffold><scaffolding><self-renew><self-renewal><social role><spongioblastoma multiforme><stem><stem-like cell><success><therapeutic resistance><therapy resistant><transcriptome sequencing><transcriptomic sequencing><translational model><treatment resistance><tumor><tumor heterogeneity><tumor immune microenvironment><tumor microenvironment><tumor progression><tumor-immune system interactions>