Glioblastoma (GBM) is an aggressive and deadly brain cancer with a one year median survival due tothe lack of effective targeted treatments. Our goal is to develop a small molecule inhibitor targeting RPN13protein in the 19S proteasome complex as a new drug for GBM. RPN13 is a proteasome ubiquitin receptor that recognizes ubiquitin-conjugated proteins that are thus tagged for degradation via the 20S proteasome enzymaticcomplex. GBM is highly sensitive to proteasome inhibition due to its aggressive growth and accumulation of misfolded polyubiquitinated proteins that is insufficiently managed despite increased proteasome levels andenhanced proteasome activity (i.e. proteotoxic stress). Up Therapeutics judiciously designed drug-like RPN13inhibitors to overcome limitations in the prototype RPN13 inhibitor RA190 identified at Johns Hopkins University. We selected Up284 as lead compound based upon our preliminary studies showing drug-like characteristics,specificity (binding to Cys88 of RPN13), and proteasome inhibition that produces a cytotoxic accumulation ofpolyUb proteins, ER stress, and reactive oxygen species. Up284 treatment selectively triggers apoptosis in solidtumor types including GBM cell lines and oncospheres. A suitable Up284 formulation was selected by measuringaqueous solubility, stability and on-target activity in mice imaged using a proteasome-dependent in vivo reporter.Up284 can be administered i.v. or orally, and it penetrates through the BBB. As a proof of concept for treatment of GBM, Up284 demonstrated on-target activity in intracranial syngeneic GL261 tumor model by inhibiting proteasome function in tumor tissues. Up284 also regressed tumors in syngeneic, xenograft and spontaneous models of ovarian cancer with acceptable safety profile. Pilot toxicological data indicated Up284 is relatively well tolerated with no evidence of behavioral abnormalities and normal CBC and blood chemistry panel. Given the potential of Up284 as a new cancer drug and GBM as its lead indication, we propose:Goal1a. Determine Up284 dose required in the brain to kill GBM oncospheres (1-3 months): Renewable oncosphere formation in culture is a defining characteristic of certain brain tumor initiating cells. Up284 activityagainst the growth of GBM oncospheres in the presence and absence of an in vitro BBB layer will be tested.Goal1b. Up284 plasma and tissue distribution studies after IV vs Oral delivery in male & female CD1 mice(3-6 months): Milestones: Identify GBM therapeutic levels needed in the brain and how to deliver Up284 to achieve them. Goal2. Efficacy of Up284 against the growth of orthotopic GBM oncospheres in male &female nude mice (6-12 months). We will test Up284 activity against an intracranial orthotopic transplantation model using firefly luciferase-expressing Br23C oncospheres in nude female mice bearing intracranial Br23Concospheres or nude male mice bearing JHH-27 oncospheres, a temozolamide resistant model. Milestones:Demonstrate that Up284 provides RECIST-defined complete response (CR) or partial response (PR) against tumor growth using oncosphere-derived GBM models in mouse brain.
Public Health Relevance Statement: Project Narrative. The objective of this STTR phase I project is to develop a small molecule inhibitor targeting ubiquitin proteasome receptor RPN13 as a new targeted drug for treatment of patients with the aggressive and rapidly fatal brain cancer glioblastoma.
Project Terms: developmental, Behavioral, Image, imaging, cost, burden of illness, burden of disease, disease burden, years of life lost to disability, years of life lost to disease, virtual, cancer type, Resistance, resistant, novel therapeutics, new drug treatments, new drugs, new therapeutics, new therapy, next generation therapeutics, novel drug treatments, novel drugs, novel therapy, prototype, tumor, new therapeutic target, new drug target, new druggable target, new pharmacotherapy target, new therapy target, novel drug target, novel druggable target, novel pharmacotherapy target, novel therapeutic target, novel therapy target, FDA approved, standard care, standard treatment, Biological Markers, bio-markers, biologic marker, biomarker, endoplasmic reticulum stress, ER stress, Regimen, targeted treatment, targeted drug therapy, targeted drug treatments, targeted therapeutic, targeted therapeutic agents, targeted therapy, targeted cancer therapy, Formulation, novel anticancer drug, new anti-cancer agent, new anticancer agent, new anticancer drug, new antineoplastic, new cancer drug, novel anti-cancer agent, novel anti-cancer drug, novel anticancer agent, novel antineoplastic, novel cancer drug, small molecule inhibitor, Growth Factor, Growth Agents, Growth Substances, Proteins Growth Factors, proteotoxicity, proteotoxic, experimental study, experiment, experimental research, in vivo imaging system, IVIS SpectrumCT, IVIS imaging, IVIS optical imaging, IVIS spectral imaging, IVIS spectrum, IVIS system, transplant model, Financial Hardship, financial burden, financial distress, financial strain, financial stress, Chemotherapy and/or radiation, Chemotherapy and Radiation, cost estimate, cost estimation, Aftercare, After Care, After-Treatment, post treatment, Alkylating Agents, Alkylators, inhibitor, Back, Dorsum, Biological Assay, Assay, Bioassay, Biologic Assays, Blood Chemical Analysis, Blood Chemical Analyses, blood chemistry, Blood - brain barrier anatomy, Blood-Brain Barrier, Hemato-Encephalic Barrier, bloodbrain barrier, Brain, Brain Nervous System, Encephalon, Brain Neoplasms, Brain Neoplasia, Brain Tumors, tumors in the brain, Cell Death, necrocytosis, Cell Line, CellLine, Strains Cell Lines, cultured cell line, Cells, Cell Body, Chemistry, High Pressure Liquid Chromatography, HPLC, High Performance Liquid Chromatography, High Speed Liquid Chromatography, Cisplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cisplatina, Cisplatinum, Cysplatyna, Dichlorodiammineplatinum, Peyrone's Chloride, Peyrone's Salt, Platinum Diamminodichloride, cis dichlorodiammineplatinum, cis platinum compound, cis-Diaminedichloroplatinum, cis-Diamminedichloroplatinum, cis-Diamminedichloroplatinum(II), cis-Dichlorodiammineplatinum(II), cis-Platinum, DNA, Deoxyribonucleic Acid, Drug Design, Pharmaceutical Preparations, Drugs, Medication, Pharmaceutic Preparations, drug/agent, Family, Female, Glioblastoma, Grade IV Astrocytic Neoplasm, Grade IV Astrocytic Tumor, Grade IV Astrocytoma, glioblastoma multiforme, spongioblastoma multiforme, Goals, Growth, Generalized Growth, Tissue Growth, ontogeny, In Vitro, Lead, Pb element, heavy metal Pb, heavy metal lead, male, Nude Mice, Athymic Mice, Athymic Nude Mouse, Mus, Mice, Mice Mammals, Murine, Patients, Pharmacology, Phenotype, Blood Plasma, Plasma Serum, Reticuloendothelial System, Serum, Plasma, Plasma, Production, Proteins, Radiotherapeutics, Radiotherapy, radiation treatment, treatment with radiation, Radiation therapy, Safety, Cell Communication and Signaling, Cell Signaling, Intracellular Communication and Signaling, Signal Transduction Systems, Signaling, biological signal transduction, Signal Transduction, Solubility, Specificity, Stress, Survival Rate, Testing, Time, Drug or chemical Tissue Distribution, Tissue Distribution, Tissues, Body Tissues, Toxicology, Translations, Ubiquitin, APF-1, ATP-Dependent Proteolysis Factor 1, HMG-20, High Mobility Protein 20, Universities, temozolomide, Temodal, Temodar, methazolastone, Measures, Serum-Free Culture Media, Protein-Free Media, Serum-Free Media, Treatment Cost, Malignant neoplasm of brain, Brain Cancer, Malignant Tumor of the Brain, Apoptosis, Apoptosis Pathway, Programmed Cell Death, Reactive Oxygen Species, Active Oxygen, Oxygen Radicals, Pro-Oxidants, base, Phase, Medical, 20S Catalytic Proteasome, 20S Core Proteasome, 20S Proteasome, 20S Proteosome, Macropain, Macroxyproteinase, Multicatalytic Proteinase, Prosome, Proteasome, Proteasome Endopeptidase Complex, Proteosome, multicatalytic endopeptidase complex, Solid Tumor, Solid Neoplasm, Therapeutic, Photinus luciferin 4 monooxygenase, Firefly Luciferases, Genetic, Normal Tissue, Normal tissue morphology, Reporter, Hematologic Cancer, Hematologic Malignancies, Hematological Malignancies, Hematological Neoplasms, Hematological Tumor, Hematopoietic Cancer, Malignant Hematologic Neoplasm, Hematologic Neoplasms, Complex, Dependence, Oral, Route, Pattern, Tumor Tissue, Heterograft, Heterologous Transplantation, Xenograft, Xenotransplantation, xeno-transplant, xeno-transplantation, Xenograft procedure, Operative Procedures, Surgical, Surgical Interventions, Surgical Procedure, surgery, Operative Surgical Procedures, meetings, Receptor Protein, receptor, success, mortality statistics, tumor growth, attenuation, aqueous, Toxicities, Toxic effect, Histopathology, complete response, In complete remission, novel, Modeling, ovarian neoplasm, Ovarian Tumor, Ovary Neoplasms, Ovary Tumor, Malignant Ovarian Neoplasm, Malignant Ovarian Tumor, Malignant Tumor of the Ovary, Ovary Cancer, ovarian cancer, Malignant neoplasm of ovary, Molecular Interaction, Binding, Bortezomib, small molecule, Proteasome Inhibitor, Dose, Core Facility, cytotoxic, Data, Proteasome Inhibition, in vivo, Apoptotic, BALB/c Nude Mouse, BALB/c Nude, Small Business Technology Transfer Research, STTR, partial response, Characteristics, Development
