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Principal Investigator: Chad V Pecot
Organization: ENFUEGO THERAPEUTICS INC.
Fiscal Year: 2020
Award: $224,995
Funding agency: National Cancer Institute
Research Summary:
The KRAS proto-oncogene is one of the most critical genes in cancer, yet it has also proven to be among the
most elusive. Nearly all (98%) of KRAS missense mutations occur in codons 12 or 13, which leads to constitutive
KRAS activation and promotion of numerous cancer hallmarks. Although kinase inhibitors have revolutionized
treatment of some subsets of cancers driven by other molecular aberrations, the lack of such success in mutant
KRAS-driven cancers has led KRAS itself being widely regarded as “undruggable”. Although there are G12C
inhibitors currently being developed, these therapies are limited to only one KRAS mutation, accounting for only
~12% of KRAS mutations, and therefore limited in therapeutic scope. We have established a C Corporation,
EnFuego Therapeutics, Inc. to address the growing number of “undruggable” targets in cancer by using RNA
interference (RNAi)-based therapeutics. RNAi is attractive because it enables silencing of cancer targets that
cannot be inhibited using conventional approaches. We have several lines of evidence that our lead drug, EFTX-
001, potently silences the majority of missense mutations and spares the WT sequence. Using an FDA-approved
lipid nanoparticle (LNP) delivery system, we have already found impressive therapeutic potential for delivering
EFTX-001 in lung cancer models with no detectable toxicity. Taken together, key questions arise, such as: 1)
Which KRAS missense mutations are most potently targeted by EFTX-001? 2) What toxic effects does LNP-
EFTX-001 have on healthy adult tissue (e.g. liver, kidney and bone marrow)? 3) What is the therapeutic index of
LNP-EFTX-001 in KRAS-dependent cancer models? We hypothesize that LNP-EFTX-001 will potently silence
multiple clinically-relevant KRAS mutations in lung and colon cancers while sparing the wild-type sequence;
consequently, inhibiting tumor progression with a highly satisfactory toxicity profile. The objectives of this
proposal are: 1) to define how potently EFTX-001 targets the most common KRAS mutations while sparing the
WT sequence, 2) to evaluate the effects of EFTX-001 on MAP kinase signaling and cell viability, 3) use in vitro
and in vivo models to determine the therapeutic index of silencing mutant versus WT KRAS in cancer and adult
tissues, respectively.
Terms: <21+ years old><Accounting><Address><Adult><Adult Human><Assay><Bioassay><Biologic Assays><Biological Assay><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><C-K-RAS><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Model><Cancer-Promoting Gene><CancerModel><Cancers><Cell Communication and Signaling><Cell Line><Cell Signaling><Cell Survival><Cell Viability><CellLine><Cellular Oncogene><Cessation of life><Chromosomal, Gene, or Protein Abnormality><Clinical Trials><Codon><Codon Nucleotides><Collaborations><Colon><Colon Cancer><Colon Carcinoma><Colonic Carcinoma><Cytogenetic or Molecular Genetic Abnormality><Death><Development><Dose><Dose-Limiting><Drugs><Europe><FDA approved><Formulation><Genes><Genetic Abnormality><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><In Vitro><International><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kidney><Kidney Urinary System><Lead><Legal patent><Licensing><Liver><Liver Cells><Lung Adenocarcinoma><MAP kinase><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Medication><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Missense Mutation><Mitogen-Activated Protein Kinases><Modeling><Molecular Abnormality><Murine><Mus><Mutate><Mutation><Neoplasm Metastasis><Oncogene K-Ras><Oncogenes><Oncology><Oncology Cancer><Pancreas Cancer><Pancreatic Cancer><Patents><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proto-Oncogenes><Pulmonary Cancer><Pulmonary malignant Neoplasm><Quelling><RASK2><RNA Interference><RNA Silencing><RNA delivery><RNAi><Renal Cell><Research><SBIR><Secondary Neoplasm><Secondary Tumor><Sequence-Specific Posttranscriptional Gene Silencing><Signal Transduction><Signal Transduction Systems><Signaling><Small Business Innovation Research><Small Business Innovation Research Grant><Strains Cell Lines><System><Technology><Testing><Therapeutic><Therapeutic Index><Thermodynamic><Thermodynamics><Tissues><Toxic effect><Toxicities><Transforming Genes><Treatment Efficacy><Universities><Work><adulthood><base><biological signal transduction><c-ONC><cancer in the colon><cancer metastasis><cancer progression><clinical relevance><clinically relevant><cultured cell line><developmental><drug/agent><efficacy study><experiment><experimental research><experimental study><first in man><first-in-human><genome mutation><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><human disease><in vivo><in vivo Model><in vivo evaluation><in vivo testing><inhibitor><inhibitor/antagonist><intervention efficacy><kidney cell><kinase inhibitor><lead candidate><lipid nanoparticle><lung cancer><mRNA><malignancy><molecular aberrations><mutant><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neoplasm progression><neoplasm/cancer><neoplastic progression><pancreatic malignancy><personalized drugs><precision drugs><precision medicine><precision-based medicine><protooncogene><renal><success><systemic toxicity><therapeutic efficacy><therapeutically effective><therapy efficacy><tumor><tumor cell metastasis><tumor progression><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>