The proto-oncogene KRAS is one of the most critical genes in cancer, yet, as a drug target, it has proven to be among the most elusive. A remarkable 30% of lung adenocarcinomas, 45% of colon, and 98% of pancreatic cancers are driven by KRAS mutations. These cancers account for the top 3 causes of cancer-related deaths in the United States. Most cancer associated KRAS mutations result in a constitutively active protein, which drives aberrantly high downstream signaling of pro-proliferative and pro-survival effectors including the MAPK and PI3K pathways. Kinase inhibitors have revolutionized treatment of many cancers driven by other molecular aberrations, yet, unfortunately a lack of such success in KRAS-driven cancers has led to KRAS itself to be widely regarded as "undruggable". EnFuego Therapeutics, Inc. (EFTX) was founded to address the growing number of "undruggable" targets in cancer using RNA interference (RNAi)-based therapeutics. RNAi is particularly attractive for KRAS targeting because it can be optimized to enable selective silencing of mutant transcripts while sparing wild type transcripts, which is important for maintaining normal function in nonmalignant tissue. Mutation-specific therapeutics against KRAS are under development by several companies such as Amgen and Mirati, and rely on small molecules (specific only to G12C mutations). Unlike prior RNAi strategies in cancer, the EFTX approach employs nucleotide modification and ligand conjugation chemistries to promote in vivo stability and affinity-based targeting in cancer cells. In particular, ligand conjugation represents a significant advantage over legacy delivery technologies such as lipid nanoparticles. We have shown that EnFuego siRNAs targeting mutant KRAS transcripts result in: 1) reduced oncogenic MAPK signaling, 2) reduced cancer cell proliferation, and 3) reduced tumor burden in murine cancer models. Based on these preliminary data, this Fast Track program will further develop EFTX siRNA technologies for targeting mutant KRAS in humans. During Phase I, we will focus on optimization of fully chemically modified (FM) siRNA compounds that potently and specifically silence mutant G12V transcripts, exhibit serum stability and immune stealth, and inhibit downstream cancer cell signaling. Two to three FM siRNAs will be selected as lead compound candidates for progression to Phase II studies. Phase II Specific Aims will focus on optimization of pharmacokinetics, tissue targeting, and efficacy in murine models of metastatic lung cancer. These data will inform the selection of a single candidate for scale up and a 4-week GLP safety assessment study. As such, this Fast Track program will accelerate progression of this novel therapeutic strategy toward filing an Investigational New Drug application for metastatic lung cancer therapy.
Public Health Relevance Statement: Project Narrative KRAS mutations represent one of the most common molecular etiologies of cancer and confer high mortality rates in a broad range of organ malignancies including lung, colon, and pancreas. Selectively eliminating mutant forms of the protein while retaining normal nonmalignant KRAS protein is extremely challenging for conventional therapeutic strategies. EnFuego Therapeutics has developed a novel, ligand- directed siRNA-based technology capable of suppressing mutant KRAS while sparing wild type transcripts. These compounds also exhibit hallmark characteristics of effective targeted therapies, including serum stability, cancer growth inhibition, and abrogation of oncogenic downstream KRAS signaling. This Fast Track proposal will focus on the optimization of select EnFuego compounds which target G12V mutant KRAS in lung cancer, a mutation that is intractable for other therapeutic strategies and contributes 22% of all KRAS-associated lung cancer cases.
Project Terms: Acceleration; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Chemistry; Colon; Cessation of life; Death; Investigational Drugs; Investigational New Drugs; Exhibits; Genes; Genetic Engineering; Genetic Engineering Biotechnology; Genetic Engineering Molecular Biology; Recombinant DNA Technology; genetically engineered; Growth; Generalized Growth; Tissue Growth; ontogeny; Half-Life; Human; Modern Man; In Vitro; Kidney; Kidney Urinary System; renal; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Ligands; Liver; hepatic body system; hepatic organ system; Lung; Lung Respiratory System; pulmonary; Lung Neoplasms; Lung Tumor; Pulmonary Neoplasms; mortality; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nucleic Acids; Nucleotides; Oligonucleotides; Oligo; oligos; Pancreas; Pancreatic; Drug Kinetics; Pharmacokinetics; Phosphorylation; Protein Phosphorylation; Proteins; Proto-Oncogenes; Cellular Oncogene; c-ONC; protooncogene; Epidermal Growth Factor Receptor; EGF Receptor; EGFR; ERBB Protein; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone Receptors; HER1; TGF-alpha Receptor; Transforming Growth Factor alpha Receptor; Urogastrone Receptor; c-erbB-1; c-erbB-1 Protein; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; proto-oncogene protein c-erbB-1; Endosomes; Receptosomes; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Vertebral column; Spinal Column; Spine; backbone; Technology; Testing; Thermodynamics; Thermodynamic; Tissues; Body Tissues; United States; Lung Adenocarcinoma; Investigational New Drug Application; Organ; improved; Phase; biologic; Biological; Chemicals; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; Blood Serum; Serum; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; Chromosomal, Gene, or Protein Abnormality; Cytogenetic or Molecular Genetic Abnormality; Genetic Abnormality; molecular aberrations; Molecular Abnormality; Therapeutic; fluid; liquid; Liquid substance; cancer cell; Malignant Cell; Malignant neoplasm of pancreas; Malignant Pancreatic Neoplasm; Pancreas Cancer; Pancreatic Cancer; pancreatic malignancy; programs; Hour; Immune; Immunes; subcutaneous; subdermal; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Ablation; Cell Proliferation; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; mutant; neoplastic cell; Tumor Cell; success; phosphorothioate; Toxic effect; Toxicities; novel; Pharmacodynamics; Modeling; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; Short interfering RNA; siRNA; Small Interfering RNA; Post-Transcriptional Gene Silencing; Posttranscriptional Gene Silencing; Quelling; RNA Silencing; RNAi; Sequence-Specific Posttranscriptional Gene Silencing; RNA Interference; kinase inhibitor; locked nucleic acid; Preparedness; Readiness; small molecule; PIK3CG gene; 1-Phosphatidylinositol 3-Kinase; PI-3 Kinase; PI3-Kinase; PI3CG; PI3KGamma; PI3k; PIK3; PIK3CG; Phosphatidylinositol 3-Kinase; Phosphatidylinositol-3-OH Kinase; Phosphoinositide 3-Hydroxykinase; PtdIns 3-Kinase; Type I Phosphatidylinositol Kinase; Type III Phosphoinositide 3-Kinase; KRAS2 gene; 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; MAP Kinase Gene; Extracellular Signal-Regulated Kinase Gene; MAPK; Mitogen-Activated Protein Kinase Gene; Address; Tumor Burden; Tumor Load; Affinity; Data; in vivo; Cancer Etiology; Cancer Cause; Cancer Model; CancerModel; Non-Malignant; nonmalignant; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Transcript; Xenograft Model; xenograft transplant model; xenotransplant model; Characteristics; Molecular; Modification; Development; developmental; safety study; Pathway interactions; pathway; knockdown; knock-down; Biodistribution; scale up; Cancer cell line; Oncogenic; murine model; mouse model; tumor; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; phase II study; phase 2 study; Drug Targeting; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; preservation; phase 2 evaluation; phase II evaluation; phase II testing; phase 2 testing; lipid based nanoparticle; lipid nanoparticle; safety assessment; PK/PD; pharmacokinetics and pharmacodynamics; lung cancer cell; PDX model; Patient derived xenograft; patient derived xenograft model; feasibility testing; KRAS driven oncogenesis; KRAS-driven tumorigenesis; KRAS-mediated tumorigenesis; oncogenic KRAS; KRAS oncogenesis; Circulation
