Modèles pour le carcinome du poumon non à petites cellules
Erin Trachet | Sr. Scientific Advisor, Oncology / Sr. Manager, Proposal Development
Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women. About 14 % of all new cancers are lung cancer. The American Cancer Society's estimates for lung cancer in the United States for 2018 are:
- About 234 030 new cases of lung cancer (121 680 in men and 112 350 in women)
- About 154 050 deaths from lung cancer (83 550 in men and 70 500 in women)
There are two main types of lung cancer, non-small cell (NSCLC) and small cell (SCLC) lung cancer. NSCLC represents ~85 % of all lung cancer cases. Lung cancer mainly occurs in older people, with diagnosis occurring at age 65 or older.
Overall, the chance that a man will develop lung cancer in his lifetime is about 1 in 15; for a woman, the risk is about 1 in 17. These numbers include both smokers and non-smokers. For smokers the risk is much higher, while for non-smokers the risk is lower. The lung cancer rate has been dropping among men over the past few decades, but only for about the last decade in women. Many contribute this decline to the significant anti-smoking campaigns and the efforts to keep young adults from ever trying it.
As with all cancer prognoses it is highly dependent on how early the cancer is found. If discovered early, the prognosis can be very favorable, even curative. However, since many people live asymptomatically for many years early detection is challenging.
Treatment options for NSCLC are surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. In many cases, a combination of multiple treatment types is used. In the last few years there have been several new targeted and immune based therapies approved by the FDA. These drugs are the result of hundreds of hours of preclinical research evaluating novel therapies in cell and animal models.
NSCLC continues to be a histotype of great interest in the research community due to the high rate of new cases diagnosed annually. Targeted therapy has been widely successful but acquired resistance is a recurring issue. To support preclinical research needs, Covance has several well optimized non-small cell lung cancer lines (See Table 1). In this Model Spotlight we highlight a few of our more commonly used lines. (For a complete list of our tumor models click here.)
HCC827 was isolated from a 39 year old Caucasian woman. This cell line harbors an exon 19 deletion within the EGFR gene.1 Clinically, this mutation is a strong predictor for sensitively to EGFR inhibitors. As a preclinical model this cell line would be suitable for screening novel EGFR inhibitors. The model is most commonly utilized following subcutaneous (SC) implant; however, Covance has also transfected this line with luciferase to allow for bioluminescence imaging to monitor disease progression following direct implant into the lung. Tumor growth is reliable following either SC or orthotopic (OT) lung implant. In both implant sites there is minimal animal-to-animal variability, tumor volume doubling is every 8 days (for both), and the mice typically reach evaluation size (~750mm3 or 5E+09 p/s) in approximately 30 days post implant (See Figures 1, 2 [SC] and 3, 4 [OT]).
NCI-H1975 was established from a female non-smoker. This cell line is of interest to the research community because of its L858R/T790M mutational status. The T790M acquired mutation is found in 50-60 % of NSCLC patients that become resistant to 1st and 2nd generation EGFR inhibitors.1,2 Therefore, this model is suitable for evaluating novel 3rd generation EGFR inhibitors, such as compounds that bind to EGFR regardless of the mutational changes that have occurred, or compounds that bind irreversibly. Also, this model would be valuable when evaluating combination therapies with EGFR inhibitors looking to mitigate resistance to treatment. Subcutaneous tumor growth of the model is reliable and consistent, with tumor volume doubling every 3-4 days and typically reaching evaluation size (~750mm3) in approximately 15 days post implant (See Figures 5 and 6).
The NCI-H1975 line has also been transfected with luciferase to allow for bioluminescence imaging to monitor disease progression. To mimic lung to brain metastases, we have implanted this line intracranially and treated with radiation, similar to the clinical setting. The control tumor growth was very aggressive with animals presenting signs of progressive disease (weight loss) by day 14 and the median day of death was day 22. However, radiation therapy was very effective in this model producing a 160 % increase in overall life span and 88 % partial responders (see Figures 7 and 8).
NCI-H460 was isolated from the pleural fluid of a Caucasian male in 1982. Based on the ATCC characterization, this cell line expresses p53 mRNA at levels close to healthy tissue and expresses wild-type EGFR. However, H460 has a mutant KRAS gene which is common for NSCLC and can also be associated with targeted therapy resistance. H460 also has mutant PI3CA.3 These genetic mutations make this model appealing for EGFR and mTOR combination therapy studies as well as further evaluation of the KRAS mutation on treatment response or resistance. We have used this model internally to evaluate chemotherapies such as docetaxel (See Figures 9 and 10). Docetaxel therapy was well tolerated but ineffective leaving a significant dynamic range for improvement. The control subcutaneous tumor growth is very aggressive and reliable, with tumor volume doubling every 1-2 days and typically reaching evaluation size (~750mm3) in approximately 11 days post implant (See Figures 9 and 10).
Please contact us if you are interested in discussing any of our human NSCLC models.
1Shuhang Wang, Shundong Cang, and Delong Liu J Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer J Hematol Oncol. 2016; 9: 34.
2Yun M, Kim EO, Lee D, Kim JH, Kim J, Lee H, Lee J, Kim SH Melatonin sensitizes H1975 non-small-cell lung cancer cells harboring a T790M-targeted epidermal growth factor receptor mutation to the tyrosine kinase inhibitor gefitinib. Cell Physiol Biochem. 2014;34(3):865-72. doi: 10,12/000366305. Epub 2014 Aug 21.
3Girard L, et al. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res. 60: 4894-4906, 2000. PubMed: 10987304.
Note: Studies were performed in accordance with applicable animal welfare regulations in an AAALAC-accredited facility Note: Studies were performed in accordance with applicable animal welfare regulations in an AAALAC-accredited facility