Mutant forms of KRAS are a key driver in human tumors but remain partially refractory to therapeutic intervention. After over three decades of research, only a single inhibitor (sotorasib) targeting a single mutation (KRASG12C) have reached market. The difficulty for developing small molecule KRAS inhibitors has heightened the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed Brushield conjugate, which substantially enhances the antitumor activity of antisense oligonucleotides by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and tumor accumulation, allowing for a much lower dosage to be used compared to conventional methods. The conjugate also suppresses nearly all side effects associated with traditional nucleic acid drugs by reducing unwanted nucleic acid-protein interactions. The goal of this proposal is to lay the groundwork for translating the technology towards the clinic. In Phase I, we will optimize the structure of the Brushield conjugate, and enhance current indication using a panel of non-small cell lung cells and mouse xenograft models. Upon reaching set quantitative milestones, we will subject the conjugate to more relevant animal models (orthotopic and patient-derived xenograft models), and perform tolerability and pharmacokinetic studies in mice and monkeys (Phase II). These studies will allow us to pursue an IND filing at the end of the project.
Public Health Relevance Statement: Project Narrative Mutated KRAS is a highly prevalent oncoprotein driving a number of cancers, but pharmacological inhibition is limited to only the G12C mutant despite over thirty years of research. Here, we propose to develop an antisense oligonucleotide-based therapeutic agent which takes advantage of our proprietary delivery technology. Building upon strong efficacy indication in non-small cell carcinoma mouse models, we will perform additional structure optimizations, conduct toxicology/pharmacology studies in both mice and non-human primates, and obtain additional indications in advanced preclinical animal models.
Project Terms: inhibitor; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Automobile Driving; driving; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Blood; Blood Reticuloendothelial System; Blood Coagulation Disorders; Coagulation Disorder; Coagulopathy; bleeding disorder; clotting disorder; Body Weight; Non-Small-Cell Lung Carcinoma; NSCLC; NSCLC - Non-Small Cell Lung Cancer; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Carcinoma; nonsmall cell lung cancer; Cells; Cell Body; Clinical Chemistry; Complement; Complement Proteins; Deoxyribonucleases; DNA Nucleases; DNase; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Exhibits; Gene Expression Regulation; Gene Action Regulation; Gene Regulation; Gene Regulation Process; Genes; Goals; Half-Life; Human; Modern Man; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Immunity; Immunization; Immunologic Sensitization; Immunologic Stimulation; Immunological Sensitization; Immunological Stimulation; Immunostimulation; In Vitro; Inflammation; Kidney; Kidney Urinary System; renal; Libraries; Liver; hepatic body system; hepatic organ system; Lung; Lung Respiratory System; pulmonary; Macaca fascicularis; Cynomolgus Monkey; Cynomolgus macaque; M fascicularis; M. fascicularis; Crab-Eating Macaque; Crab-Eating Monkey; Methods; Monkeys; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nucleic Acids; Oligo; oligos; Oligonucleotides; Cancer Genes; Cancer-Promoting Gene; Transforming Genes; Oncogenes; Pharmacokinetics; Drug Kinetics; Pharmacology; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Macrogols; Polyethylene Oxide; Polyethyleneoxide; Polyoxyethylenes; Polyethylene Glycols; Polymers; Proteins; Publishing; Research; mRNA; Messenger RNA; Safety; Signal Pathway; Spinal Column; Spine; backbone; Vertebral column; Technology; Translating; Translations; Urine; Urine Urinary System; cytokine; Antisense Oligonucleotides; Anti-Sense Oligonucleotides; Antisense Agent; anti-sense agent; anti-sense oligo; antisense oligo; Ribonuclease H; Calf Thymus Ribonuclease H; Endoribonuclease H; RNase H; Mediating; base; dosage; improved; Clinical; Refractory; Phase; Chemicals; non-human primate; nonhuman primate; Measurement; uptake; Therapeutic; Therapeutic Agents; Malignant Cell; cancer cell; Intravenous; Area Under Curve; Side; Clinic; subdermal; subcutaneous; toxic reaction in immunology; immunotoxicity; mutant; phosphodiester; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; TLR protein; Toll-Like Receptor Family Gene; Toll-like receptors; Structure; Pharmacology and Toxicology; novel; Modality; MEKs; intervention therapy; Therapeutic Intervention; Modeling; Property; response; single molecule; cancer pharmacology; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Clotting; Coagulation; Coagulation Process; small molecule; C-K-RAS; K-RAS2A; K-RAS2B; K-Ras; K-Ras 2A; K-Ras-2 Oncogene; KRAS; KRAS2; Ki-RAS; Oncogene K-Ras; RASK2; v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog; KRAS2 gene; Address; Data; immune competent; Immunocompetent; Mutate; Preclinical Models; Pre-Clinical Model; in vivo; Malignant Epithelial Cell; Carcinoma Cell; Tumor Suppression; Molecular Tumor Suppression; Xenograft Model; xenograft transplant model; xenotransplant model; Monitor; Characteristics; Molecular; Modification; Development; developmental; pre-clinical; preclinical; neglect; knock-down; knockdown; nanoparticle; nano particle; nano-sized particle; nanosized particle; mouse model; murine model; stem; tumor; alternative treatment; treatment strategy; preclinical toxicity; pre-clinical toxicity; acute toxicity; small molecule inhibitor; Oncoproteins; Oncogene Products; Oncogene Proteins; Pharmacology Study; Pharmacological Study; clinical development; Injections; side effect; safety assessment; nucleic acid-based therapeutics; nucleic acid therapy; therapeutic nucleic acids; patient derived xenograft model; PDX model; Patient derived xenograft
