Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy despite aggressive surgery and toxic chemotherapies. More effective and safer targeted drugs are urgently needed to address this unmet medical need. Compared to normal tissues, EOC exhibits aberrant proteasome function that triggers accumulation of high molecular weight polyubiqutinated and misfolded protein aggregates. Because of this unresolved proteotoxic stress, EOC cell lines are highly susceptible to proteasome inhibitors. While highly effective against liquid cancers like multiple myeloma, unfortunately the licensed 20S proteasome inhibitors, such as bortezomib, have proven ineffective against solid tumors, including EOC. This reflects limited tissue access for these peptide-based drugs and dose-limiting toxicities, notably peripheral neuropathy, thrombocytopenia and neutropenia. Up284 is a proprietary upstream (19S) proteasome inhibitor with a novel target and mechanism, RPN13 inhibition, and a structure designed to overcome the limitations of the licensed drugs with respect to limited potency (Up284 blocks substrate recognition and deubiquitination by the 19S rather than just one of the three 20S catalytic activities), poor activity against solid tumors (Up284 has a novel spiro structure with improved drug-like properties compared to peptide-based 20S inhibitors, and promotes antigen-representation by tumor cells), key toxicities of peripheral neuropathy (Not clinically apparent with Up284 in initial murine studies) and thrombocytopenia and neutropenia (Up284 spares the immunoproteasome and lacks these side effects). Up284 shows broad anticancer activity in vitro, including against EOC lines selected for platinum resistance, with a robust therapeutic index and a promising safety profile, and the ability to control xenograft tumor in an orthotopic mouse model of EOC. This promising data reflects our extensive medicinal chemistry effort to achieve drug-like properties and a patent has been awarded in US (pending in other countries) to cover the novel backbone and lead compounds. Murine data indicate Up284 has favorable pharmacodynamics and confirm the novel mechanism of action in vivo. By inhibiting proteasome ubiquitin receptor RPN13 function and its associated deubiquitinase activity, Up284 produces more rapid accumulation of larger molecular weight polyubiquinated protein aggregates than the 20S inhibitors. These toxic misfolded protein aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR) and thus Up284 more rapidly triggers p53-independent apoptosis than 20S inhibitor. To support an IND application to FDA, we propose: Aim 1: Assessing toxicity & Peripheral Neuropathy (PN) in mice treated IP vs IV with Up284 vs. bortezomib (months 1-3). Aim 2: Mouse clinical trial: Testing therapeutic efficacy of Up284 delivered IP vs IV against 13 ovarian PDX models (months 3-7); Aim 3: Process development, GLP manufacture, formulation stability & GLP bioanalytical method development of Up284 (months 7-24); Aims 4 & 5: GLP toxicology and safety studies of Up284 in rats & dogs (months 15-24).
Public Health Relevance Statement: Project narrative: Three new proteasome-targeting chemotherapeutic drugs reached the market in the past decade. Although these peptide-based proteasome inhibitors are effective against multiple myeloma, unfortunately they have not proven useful to treat solid tumors (e.g. Ovarian Cancer). Up Therapeutics is developing novel small molecule inhibitors that are not peptide-based and target a different component of the proteasome (RPN13) as drug candidates for the treatment of solid tumors, notably ovarian cancer.
Project Terms: Ubiquitin; APF-1; ATP-Dependent Proteolysis Factor 1; HMG-20; High Mobility Protein 20; Universities; Carboplatin; CBDCA; Carboplatino; TP53 gene; Antioncogene Protein p53; Cellular Tumor Antigen P53; Oncoprotein p53; P53; Phosphoprotein P53; Phosphoprotein pp53; Protein TP53; TP53; TRP53; Tumor Protein p53; Tumor Protein p53 Gene; p53 Antigen; p53 Genes; p53 Tumor Suppressor; protein p53; Anzatax; Asotax; Bristaxol; Paclitaxel (Taxol); Praxel; Taxol; Taxol A; Taxol Konzentrat; Paclitaxel; Apoptosis Pathway; Programmed Cell Death; Apoptosis; method development; Organ; improved; Ovarian; Acute; Solid; Clinical; Biochemical; Medical; Inorganic Platinum Compounds; Platinum Agents; Platinum Compounds; 20S Catalytic Proteasome; 20S Core Proteasome; 20S Proteasome; 20S Proteosome; Macropain; Macroxyproteinase; Multicatalytic Proteinase; Prosome; Proteasome; Proteasome Endopeptidase Complex; Proteosome; multicatalytic endopeptidase complex; Susceptibility; Predisposition; Licensing; analog; Medical Oncologist; Solid Tumor; Solid Neoplasm; de-ubiquitinase; de-ubiquitinating enzyme; ubiquitin-specific isopeptidase; ubiquitin isopeptidase; Therapeutic; fluid; liquid; Liquid substance; Normal tissue morphology; Normal Tissue; cancer cell; Malignant Cell; Mantle Cell Lymphoma; Centrocytic Small-Cell Lymphoma; Lymphoma, Lymphocytic, Diffuse, Poorly-Differentiated; Mantle-Zone Lymphoma; Chemotherapy-Oncologic Procedure; Chemotherapy Protocol; Chemotherapy Regimen; Combination Chemotherapy Regimen; Quimioterapia; cancer chemotherapy; Scientist; Tumor Debulking; Debulking; cytoreductive surgery; surgical cytoreduction; tumor cytoreduction; Country; Tumor Tissue; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; experience; neoplastic cell; Tumor Cell; protein metabolism; receptor; Receptor Protein; cell killing; Toxic effect; Toxicities; Epithelial ovarian cancer; Speed; Structure; Therapeutic Index; novel; behavior test; behavioral test; Malignant Female Reproductive System Neoplasm; Female Reproductive Cancer; Gynecologic Cancer; Gynecological Cancer; Malignant Gynecologic Neoplasm; Malignant Gynecologic Tumor; Malignant Tumor of the Female Reproductive System; gynecologic malignancy; gynecological malignancy; Pharmacodynamics; Property; response; Cardiotoxicity; Cardiac Toxicity; Cardiotoxic; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; Deubiquitination; Bortezomib; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; VEGF; VEGFs; Vascular Endothelial Growth Factors; Normal Cell; Effectiveness; therapeutic testing; therapeutic evaluation; small molecule; Address; Proteasome Inhibitor; Dose; Symptoms; Data; Dose Limiting; Gynecologic Pathology; Improve Access; Proteasome Inhibition; in vivo; Cancer Model; CancerModel; Cancer Patient; Nucleosome Core Particle; Core Particle; Nucleosome Core; Validation; validations; Monitor; Process; Development; developmental; safety study; designing; design; insoluble aggregate; protein aggregate; protein aggregation; tumor xenograft; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; Cancer cell line; anti-cancer activity; anticancer activity; resistant; Resistance; neuron toxicity; neuronal toxicity; neurotoxicity; chemotherapy; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; tumor; standard of care; response to therapy; response to treatment; therapeutic response; therapy response; treatment response; in vitro activity; drug candidate; ER stress; endoplasmic reticulum stress; Regimen; Drug Targeting; targeted agent; Formulation; Peptide-based drug; therapeutic peptide; peptide drug; improved outcome; small molecule inhibitor; aberrant folded protein; aberrant folded proteins; abnormal folded protein; abnormal folded proteins; misfolded proteins; proteotoxic protein; proteotoxin; misfolded protein; proteotoxic; proteotoxicity; pre-clinical development; preclinical development; side effect; PK/PD; pharmacokinetics and pharmacodynamics; PDX model; Patient derived xenograft; patient derived xenograft model; resistant cancer; refractory cancer; Poly(ADP-ribose) Polymerase Inhibitor; PARP Inhibitor; PARP-1 inhibitor; PARPi; Poly(ADP-ribose) polymerase 1 inhibitor; manufacture; inhibitor; immunogen; Antigens; Australia; Award; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Body Weight Changes; Weight Change; CA-125 Antigen; CA-125; CA125; Cancer Antigen 125; Carbohydrate Antigen 125; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; 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; Clinical Trials; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Exhibits; Female; Goals; Half-Life; Human; Modern Man; Industry; Lead; Pb element; heavy metal Pb; heavy metal lead; Marketing; Molecular Weight; Multiple Myeloma; Plasma-Cell Myeloma; myeloma; myelomatosis; Mus; Mice; Mice Mammals; Murine; neurophysiology; neurophysiological; Neutropenia; Legal patent; Patents; Patients; Peptides; Peripheral Nervous System Diseases; PNS Diseases; Peripheral Nerve Diseases; Peripheral Nervous System Disorders; Peripheral Neuropathy; Peripheral Nerves; Greater sac of peritoneum; Peritoneal Cavity; Platinum; Platinum Black; Pt element; Proteins; Rattus; Common Rat Strains; Rat; Rats Mammals; Recurrence; Recurrent; Safety; Vertebral column; Spinal Column; Spine; backbone; Stress; Survival Rate; Testing; Thrombocytopenia; Thrombopenia; Tissues; Body Tissues; Toxicology
