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Principal Investigator: Chad V Pecot
Organization: ENFUEGO THERAPEUTICS INC.
Fiscal Year: 2023
Award: $275,645
Funding agency: National Cancer Institute
Project Summary
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.
Terms: <1-Phosphatidylinositol 3-Kinase><Ablation><Acceleration><Address><Affinity><Biodistribution><Biological><Blood Serum><Body Tissues><C-K-RAS><Cancer Cause><Cancer Etiology><Cancer Model><Cancer Treatment><Cancer cell line><CancerModel><Cancers><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cellular Oncogene><Cellular Proliferation><Cessation of life><Characteristics><Chemicals><Chemistry><Chromosomal, Gene, or Protein Abnormality><Circulation><Colon><Cytogenetic or Molecular Genetic Abnormality><Data><Death><Development><Drug Kinetics><Drug Targeting><EGF Receptor><EGFR><ERBB Protein><Endosomes><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Exhibits><Extracellular Signal-Regulated Kinase Gene><Generalized Growth><Genes><Genetic Abnormality><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Growth><HER1><Half-Life><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hour><Human><Immune><Immunes><In Vitro><Intracellular Communication and Signaling><Investigational Drugs><Investigational New Drug Application><Investigational New Drugs><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><KRAS2><KRAS2 gene><Ki-RAS><Kidney><Kidney Urinary System><Lead><Libraries><Ligands><Liquid substance><Liver><Liver Cells><Lung><Lung Adenocarcinoma><Lung Neoplasms><Lung Respiratory System><Lung Tumor><MAP Kinase Gene><MAPK><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Modification><Molecular><Molecular Abnormality><Murine><Mus><Mutation><Non-Malignant><Nucleic Acids><Nucleotides><Oligo><Oligonucleotides><Oncogene K-Ras><Oncogenic><Operative Procedures><Operative Surgical Procedures><Organ><PDX model><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PK/PD><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Pathway interactions><Patient derived xenograft><Pb element><Pharmacodynamics><Pharmacokinetics><Phase><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphorylation><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Preparedness><Protein Phosphorylation><Proteins><Proto-Oncogenes><PtdIns 3-Kinase><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><Quelling><RASK2><RNA Interference><RNA Silencing><RNAi><Readiness><Receptosomes><Recombinant DNA Technology><SBIR><Safety><Sequence-Specific Posttranscriptional Gene Silencing><Serum><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Business Innovation Research><Small Business Innovation Research Grant><Small Interfering RNA><Spinal Column><Spine><Surgical><Surgical Interventions><Surgical Procedure><TGF-alpha Receptor><Technology><Testing><Therapeutic><Thermodynamic><Thermodynamics><Tissue Growth><Tissues><Toxic effect><Toxicities><Transcript><Transforming Growth Factor alpha Receptor><Tumor Burden><Tumor Cell><Tumor Load><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><United States><Urogastrone Receptor><Vertebral column><Xenograft Model><anti-cancer therapy><anticancer therapy><backbone><biologic><biological signal transduction><c-ONC><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer therapy><cancer-directed therapy><developmental><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><feasibility testing><fluid><genetically engineered><genome mutation><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><improved><in vivo><kinase inhibitor><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><liquid><locked nucleic acid><lung cancer><lung cancer cell><malignancy><molecular aberrations><mortality><mouse model><murine model><mutant><neoplasm/cancer><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><nonmalignant><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oligos><oncogenic KRAS><ontogeny><pancreatic malignancy><pathway><patient derived xenograft model><pharmacokinetics and pharmacodynamics><phase 2 evaluation><phase 2 study><phase 2 testing><phase II evaluation><phase II study><phase II testing><phosphorothioate><preservation><programs><proto-oncogene protein c-erbB-1><protooncogene><pulmonary><renal><safety assessment><safety study><scale up><siRNA><small molecule><subcutaneous><subdermal><success><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tumor><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><xenograft transplant model><xenotransplant model>