title: Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models.
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.
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Division of Medical Physics and Biophysics, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Houari
authors.initials: H
authors.lastname: Korideck
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Christensen
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Herter
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rhee
authors.affiliation: Division of Medical Physics and Biophysics, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Ross I
authors.initials: RI
authors.lastname: Berbeco
authors.affiliation: Department of Radiology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Bennett
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kozono
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Mak
authors.affiliation: Division of Medical Physics and Biophysics, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mike Makrigiorgos
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D011829:Radiation Dosage; D011836:Radiation Tolerance; D061089:Radiotherapy, Image-Guided / Q000379:methods*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)