Abstract
Close resemblance of murine and human trials is essential to achieve the best predictive value of animal-based translational cancer research. Kras-driven genetically engineered mouse models of non-small-cell lung cancer faithfully predict the response of human lung cancers to systemic chemotherapy. Owing to development of multifocal disease, however, these models have not been usable in studies of outcomes following focal radiotherapy (RT). We report the development of a preclinical platform to deliver state-of-the-art image-guided RT in these models. Presence of a single tumour as usually diagnosed in patients is modelled by confined injection of adenoviral Cre recombinase. Furthermore, three-dimensional conformal planning and state-of-the-art image-guided dose delivery are performed as in humans. We evaluate treatment efficacies of two different radiation regimens and find that Kras-driven tumours can temporarily be stabilized upon RT, whereas additional loss of either Lkb1 or p53 renders these lesions less responsive to RT.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases
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Adenoviridae / genetics
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Animals
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Non-Small-Cell Lung / radiotherapy*
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Disease Models, Animal
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Female
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Gene Expression
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Genetic Vectors
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Humans
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Integrases / genetics
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Integrases / metabolism
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Lentivirus / genetics
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / radiotherapy*
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Male
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Mice
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics*
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Proto-Oncogene Proteins p21(ras) / metabolism
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Radiation Dosage
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Radiation Tolerance
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Radiotherapy, Image-Guided / methods*
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Treatment Outcome
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Tumor Suppressor Protein p53
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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AMP-Activated Protein Kinases
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Cre recombinase
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Integrases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)