Document text
Principal Investigator: SCOTT W. LOWE
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $463,686
Funding agency: National Cancer Institute
Genome characterization has enabled the cataloging of genes altered in human tumors and stimulated the
development of therapies that exploit these alterations. Still, functional studies are ultimately needed to interpret
and exploit the genetic variation that exists in human cancers. Furthermore, it is now apparent that cancer
phenotypes and responses to therapy are dramatically influenced by the tissue microenvironment, and hence it
is necessary to have in vivo models that accurately recapitulate both the genetics and physiology of cancers in
patients. Although existing genetically engineered mouse models (GEMMs) have been instrumental in validating
cancer-promoting mutations and developing therapeutic concepts in a physiological and relevant context, these
models are simply too slow and expensive to be broadly useful and only recapitulate a minor fraction of the
genetic lesions associated with human cancer. Driven by the need for more accurate and facile models, this
project combines CRISPR genome engineering and in vivo organ electroporation with the goal of producing the
first-in-kind collection of genetically-defined mouse models of three major epithelial malignancies. We refer to
these models as electroporation-based genetically engineered mouse models (EPO-GEMMs). EPO-GEMMs
have a range of advantages over traditional GEMMs in that they are fast, affordable, modular, highly portable,
and avoid the substantial waste associated with GEMMs produced by strain intercrossing. These models are
fully somatic, enable focal tumor development and, importantly, enable the study of tumor-host interactions by
allowing tumors to be rapidly engineered in hosts of different genetic backgrounds. Based on substantial
preliminary data to validate the EPO-GEMM concepts, our project will produce and characterize EPO-GEMMs
of stomach, prostate, and pancreatic cancer - three common human cancers for which existing mouse models
do not exist or are tedious. We will then perform a series of demonstration projects to evaluate and illustrate the
unique potential of the EPO-GEMM approach, ranging from testing the efficacy and toxicity of target inhibition,
exploring the effects of specific immune cell types on cancer initiation and progression, and using synchronous
cohorts of genetically defined cancer models to test new targeted therapies and immune oncology approaches.
Therefore, our project is of direct relevance to the overarching goals of the Oncology Models Forum, as EPO-
GEMMs constitute “translational research models that are robust representations of human biology, are
appropriate to test questions of clinical importance, and provide reliable information for patients’ benefit”. Each
of these models will be credentialed with the Oncology Model Fidelity Score and all reagents will be made
available through the NCIP Hub. We believe that the development and detailed characterization of rapid, flexible,
and immunocompetent EPO-GEMMs and the adoption of these models for pre-clinical studies will be critical for
the functional annotation of genetic variation in human cancer and greatly contribute to the implementation of
precision oncology.
Terms: <21+ years old><Address><Adoption><Adult><Adult Human><Anti-Oncogenes><Antioncogenes><Benchmarking><Best Practice Analysis><Biologic Models><Biological Markers><Biological Models><Body Tissues><CRISPR><CRISPR/Cas system><Cancer Biology><Cancer Genes><Cancer Model><Cancer Suppressor Genes><Cancer-Promoting Gene><CancerModel><Cancers><Cataloging><Catalogs><Cell Body><Cell Communication Process><Cell Line><Cell Signaling Process><CellLine><Cells><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Collection><Combination immunotherapy><Combined Modality Therapy><Communities><Credentialing><DNA seq><DNA sequencing><DNAseq><Data><Dependence><Development><Disease Progression><Electroporation><Emerogenes><Engineering><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Evaluation><FGFBR><FGFR1><FGFR1 gene><FLG Gene><FLT2 Gene><FMS-Like Gene><FMS-Like Tyrosine Kinase 2 Gene><Fibroblast Growth Factor Receptor 1 Gene><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><GEM model><GEMM model><Gastric Body Cancer><Gastric Cancer><Gastric Cardia Cancer><Gastric Fundus Cancer><Gastric Pylorus Cancer><Genes><Genetic><Genetic Alteration><Genetic Annotation><Genetic Change><Genetic Diseases><Genetic Diversity><Genetic Variation><Genetic defect><Genetically Engineered Mouse><Genome><Genome engineering><Genomics><Genotype><Goals><Host-Tumor Interaction><Human><Human Biology><Immune><Immune infiltrates><Immunes><Immunocompetent><Immunomodulation><Immunooncology><Laboratories><Lesion><Maintenance><Malignant Cell><Malignant Gastric Neoplasm><Malignant Gastric Tumor><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of pancreas><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Methods><Mice><Mice Mammals><Minor><Model System><Modeling><Modern Man><Molecular><Molecular Analysis><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><Myeloid-derived suppressor cells><Onco-Suppressor Genes><Oncogenes><Oncogenes-Tumor Suppressors><Oncogenesis><Oncology><Oncology Cancer><Organ><PDX model><Pancreas Cancer><Pancreatic Cancer><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Physiologic><Physiological><Physiology><Pre-Clinical Model><Preclinical Models><Property><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><RNA Seq><RNA sequencing><RNAseq><Reagent><Recessive Oncogenes><Regulatory T-Lymphocyte><Role><Series><Somatic Mutation><Stomach Cancer><Strains Cell Lines><Subcellular Signaling Process><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Transforming Genes><Translational Research><Translational Science><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Tumor Suppressing Genes><Tumor Suppressor Genes><adulthood><anti-cancer research><benchmark><bio-markers><biologic marker><biomarker><cancer cell><cancer cell genome><cancer diagnosis><cancer genome><cancer initiation><cancer microenvironment><cancer progression><cancer research><catalog><cell type><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><cohort><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><cultured cell line><determine efficacy><develop therapy><developmental><dual immunotherapy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><electroporative delivery><entire genome><epigenetically><evaluate efficacy><examine efficacy><flexibility><flexible><flow cytophotometry><full genome><gastric malignancy><gene electrotransfer><genetic condition><genetic disorder><genetic element><genetically engineered mouse model><genetically engineered murine model><genome mutation><genome sequencing><host neoplasm interaction><human cancer mouse model><human disease><human model><immune cell infiltrate><immune check point therapy><immune checkpoint therapy><immune competent><immune modulation><immune regulation><immune-oncology><immuno oncology><immunologic reactivity control><immunology oncology><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive myeloid cells><in vivo><in vivo Model><individualized cancer care><individualized oncology><insight><intervention development><malignancy><malignant stomach neoplasm><malignant stomach tumor><model of human><mouse model><multi-modal therapy><multi-modal treatment><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasm progression><neoplasm/cancer><neoplastic progression><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><oncoimmunology><oncosuppressor gene><pancreatic malignancy><patient derived xenograft model><patient oriented outcomes><personalized oncology><portability><pre-clinical><pre-clinical study><precision cancer care><precision cancer medicine><precision oncology><preclinical><preclinical study><prostate cancer model><prostate tumor model><regulatory T-cells><response><response to therapy><response to treatment><social role><somatic variant><standard of care><stomach fundus cancer><stomach pylorus cancer><suppressive myeloid cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapeutic target><therapy development><therapy response><tool><transcriptome sequencing><transcriptomic sequencing><translation research><translational investigation><translational study><treatment development><treatment response><treatment responsiveness><tumor><tumor behavior><tumor genome><tumor microenvironment><tumor progression><tumorigenesis><wasting><whole genome>