Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice.

Abstract

PURPOSE: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT). MATERIALS AND METHODS: Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic Kras(G12D) and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy10. Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis. RESULTS: Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARF(FL/FL) mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53(FL/FL) mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53. CONCLUSION: Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations.

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Citation

Published Version (Please cite this version)

10.3389/fonc.2013.00072

Publication Info

Perez, Bradford A, A Paiman Ghafoori, Chang-Lung Lee, Samuel M Johnston, Yifan Li, Jacob G Moroshek, Yan Ma, Sayan Mukherjee, et al. (2013). Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice. Front Oncol, 3. p. 72. 10.3389/fonc.2013.00072 Retrieved from https://hdl.handle.net/10161/16172.

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Scholars@Duke

Lee

Chang Lung Lee

Assistant Professor in Radiation Oncology

The overall goal of the Lee lab’s research program is to improve the therapeutic window of radiation therapy and the survivorship of cancer patients by minimizing acute and late effects of radiation. Our current NIH-funded projects primarily focus on defining the mechanisms underlying the regeneration of epithelial cells in the oral mucosa and the small intestines in response to radiation injury. In addition, we are developing novel medical countermeasures for gastrointestinal acute radiation syndrome as well as radiation-induced intestinal fibrosis in the scenarios of nuclear terrorism.

Badea

Cristian Tudorel Badea

Professor in Radiology

  • Our lab's research focus lies primarily in developing novel quantitative imaging systems, reconstruction algorithms and analysis methods.  My major expertise is in preclinical CT.
  • Currently, we are particularly interested in developing novel strategies for spectral CT imaging using nanoparticle-based contrast agents for theranostics (i.e. therapy and diagnostics).
  • We are also engaged in developing new approaches for multidimensional CT image reconstruction suitable to address difficult undersampling cases in cardiac and spectral CT (dual energy and photon counting) using compressed sensing and/or deep learning.


Kirsch

David Guy Kirsch

Adjunct Professor in the Department of Radiation Oncology

My clinical interests are the multi-modality care of patients with bone and soft tissue sarcomas and developing new sarcoma therapies. My laboratory interests include utilizing mouse models of cancer to study cancer and radiation biology in order to develop new cancer therapies in the pre-clinical setting.


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