非小细胞肺癌模型

AUTHOR:

Erin Trachet | Sr. Scientific Advisor, Oncology / Sr. Manager, Proposal Development

日期:

2018年2月

肺癌(小细胞和非小细胞)是男性和女性中最常见的癌症。大约14%的新癌症是肺癌。美国癌症协会2018年美国肺癌的估计是:

  • 肺癌约234,030例新患者(男性121,680和女性112,350)
  • About 154,050 deaths from lung cancer (83,550 in men and 70,500 in women)

肺癌,非小细胞(NSCLC)和小细胞(SCLC)肺癌有两种主要类型。NSCLC代表肺癌病例的〜85%。肺癌主要发生在老年人身上,诊断发生在65岁或以上。

总体而言,一个人在他的寿命中发育肺癌的可能性约为15;对于一个女人来说,风险大约是1717。这些数字包括吸烟者和非吸烟者。对于吸烟者来说,风险要高得多,而非吸烟者风险较低。在过去的几十年里,肺癌率一直在滴水,但只有关于女性的最后十年。许多人促进了这一减少的减少的反吸烟运动和让年轻人从来尝试过的努力。

与所有癌症一样,它的预期高度依赖于发现癌症的早期。如果早期发现,预后可能是非常有利的,甚至治疗。然而,由于许多人在很多年内偶然生活,因此早期发现是挑战性的。

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.(有关我们肿瘤模型的完整列表点击这里。)

肺[nsclc]
A549.
A549-LUC-C8
Calu-1
Calu-3.
HCC827
HCC827-LUC-MCH-PURO
NCI-H125
NCI-H125-LUC
NCI-H1299
NCI-H1299-P53-V138-BP100-LUC
NCI-H1650
NCI-H1703
NCI-H1703-Luc-mCh-Puro
NCI-H1975
NCI-H1975-Luc
NCI-H2110
NCI-H23
NCI-H292
NCI-H3122
NCI-H441
NCI-H460
NCI-H460-Luc2
NCI-H522
PC-9.
人类

HCC827 was isolated from a 39 year old Caucasian woman. This cell line harbors an exon 19 deletion within the EGFR gene.1临床上,这种突变是敏感性的强预测因子,敏感地抑制剂。作为临床前yaboapp体育官网模型,这种细胞系适用于筛选新的EGFR抑制剂。该模型最常利用皮下(SC)植入物;然而,Covance也用荧光素酶转染了这条线,以允许生物发光成像,以监测直接植入肺部后的疾病进展。肿瘤生长在SC或原位(OT)肺部植入后是可靠的。在两个植入物位点,动物对动物变异性最小,肿瘤体积倍增每8天(两者),小鼠通常达到评价尺寸(〜750mm3或5.0 e + 09年p / s)在大约30天implant (See Figures 1, 2 [SC] and 3, 4 [OT]).

皮下HCC827

图1:皮下HCC827平均肿瘤负担
图1:皮下HCC827平均肿瘤负担
Fig. 2: Subcutaneous HCC827 % Body Weight Change
Fig. 2: Subcutaneous HCC827 % Body Weight Change

原位HCC827

图3:原位HCC827平均肿瘤负担
图3:原位HCC827平均肿瘤负担
图4:原位HCC827%体重变化
图4:原位HCC827%体重变化

NCI-H1975

NCI-H1975是由女性非吸烟者建立的。由于其L858R / T790M的突变状态,这种细胞系对研究界感兴趣。在50-60%的NSCLC患者中发现了T790M获得的突变,该患者抵抗1st和2n代EGFR抑制剂。1,2因此,该模型适用于评估新颖3rd生成EGFR抑制剂,例如与EGFR结合的化合物,无论发生的突变变化,也无可逆转地结合的化合物。此外,当评估与寻求减轻治疗抗性的EGFR抑制剂的组合疗法时,该模型将是有价值的。模型的皮下肿瘤生长是可靠且一致的,肿瘤体积每3-4天加倍,通常达到评价大小(〜750mm3)在植入后大约15天(见图5和6)。

皮下NCI-H1975

图5:皮下NCI-H1975的平均肿瘤负担
图5:皮下NCI-H1975的平均肿瘤负担
图6:皮下NCI-H1975%体重变化
图6:皮下NCI-H1975%体重变化

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).

图7:颅内NCI-H1975的平均肿瘤负担
图7:颅内NCI-H1975的平均肿瘤负担
图8:颅内NCI-H1975%的体重变化
图8:颅内NCI-H1975%的体重变化

NCI-H460

从1982年从白种人男性的胸腔流体中分离NCI-H460.根据ATCC表征,该细胞系在靠近健康组织的水平下表达p53 mRNA,表达野生型EGFR。然而,H460具有突变KRA基因,其对于NSCLC常见,并且也可以与靶向治疗抵抗有关。H460还具有突变体pi3ca。3These 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)在植入后大约11天(见图9和10)。

图9:皮下NCI-H460平均肿瘤负担
图9:皮下NCI-H460平均肿瘤负担
图10:皮下NCI-H460%体重变化
图10:皮下NCI-H460%体重变化

联系我们if you are interested in discussing any of our human NSCLC models.

1王王,顺东沧,德龙刘建第三代抑制剂靶向EGFR T790M突变在先进的非小细胞肺癌J Hematol Oncol中。2016;9:34。
2Yun M,Kim Eo,Lee D,Kim JH,Kim J,Lee H,Lee J,Kim Sh Melatonin致敏H1975非小细胞肺癌细胞,涉及酪氨酸激酶抑制剂Gefitinib的T790M靶向表皮生长因子受体突变。细胞生物学生物化学。2014; 34(3):865-72。DOI:10.1159 / 000366305。EPUB 2014 8月21日。
3Girard L等人。肺癌的基因组异位型鉴定了新的等位基因损失区域,小细胞肺癌和非小细胞肺癌之间的差异,以及基因簇聚类。癌症res。60:4894-4906,2000。PubMed:10987304。
注意:根据AAALAC认可的设施在AAALAC认可的设施中的适用性动物福利法规进行研究注意:研究是根据AAALAC-CORCREDITED设施的适用的动物福利法规进行