Abstract 2973: Mouse models of lung cancer mediated by lentiviral gene delivery

Abstract

Abstract Lung cancer, the leading cause of cancer deaths, is responsible for 1.4 million lives lost worldwide every year. Good animal models that can faithfully recapitulate the human disease are in great need for pre-clinical studies. Based on the different responses to treatment, lung cancer is divided into two major classes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Adenocarcinoma (AdC) and squamous cell lung cancer (SqCC) are two major sub-types of NSCLC. We have successfully developed a novel lentiviral gene delivery system to study the initiation and development of all these lung cancers. We used CA2Cre-shp53 lentiviral vector to initiate lung adenocarcinoma in LSL-KrasG12D mice and proved the importance of NF-κB/IKK2 pathway in tumor cell proliferation. To search for novel tumor suppressors in lung cancer, we incorporated an shRNA library targeting ∼5000 cell signal genes into our CA2Cre lentivector and did the screening in the mice. We have identified several dozens of candidates and are validating these genes back in animals. SCLC is the most malignant form of lung cancer with a five-year survival less than 6%. A mouse model with p53/Rb deletions activated by Adeno-Cre has been established in Berns lab. To improve the model and study other genes that are frequently mutated in human SCLC, we designed a single lentiviral vector to deliver oncogenes (L-myc etc.) and shRNAs against tumor suppressors (p53, Rb etc) and successfully initiated SCLC in wild-type mice. Furthermore, we included luciferase or fluorescence protein genes in the same vector to follow tumor growth and metastasis in the live animal. Using this new model, we are now studying the crosstalk of multiple mutations in the SCLC development. SqCC has not been well modeled by genetic approaches. Interestingly, when we gave KrasG12D-shp53 lentiviral vector after lung tissue damage induced by naphthalene, the mice quickly developed squamous tumors in the big bronchi other than adenocarcinomas in the peripheral lung. Kras mutations are actually not common in human SqCC patients, so we are now optimizing the model and see if more relevant genetic changes such FGFR1 amplification can also induce this type of lung cancer in mice. We hope that our unique lentiviral tool can simplify and accelerate the lung cancer study to understand the big signal pathway complex leading to tumorigenesis and metastasis in the lung and search for new therapies for this deadly human disease. Citation Format: Yifeng Xia, Narayana Yeddula, Eugene Ke, Mathias Leblanc, Inder Verma. Mouse models of lung cancer mediated by lentiviral gene delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2973. doi:10.1158/1538-7445.AM2014-2973