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对肿瘤细胞系进行药物筛查

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发表于 2017-6-5 19:43:51 | 显示全部楼层 |阅读模式
我看到一篇nature medicine文章里面提到了这个对肿瘤细胞系进行药物筛查文章链接:https://www.nature.com/nm/journal/v21/n6/full/nm.3855.html

首先,肿瘤细胞系是:

We assembled a panel of 14 patient-derived DIPG cell cultures, created using neurosphere and adherent models and obtained from both biopsy and autopsy samples (Fig. 1a), representing the breadth of DIPG cell cultures available worldwide at the initiation of the study.

其次,药物是:
Using this DIPG culture panel, we screened 83 drugs selected by pediatric neurooncologists as either promising targeted agents for cancer or traditional chemotherapeutic agents in use for pediatric brain tumor therapy.
结果是:We found sensitivity to a limited number of drugs (14/83 compounds demonstrated activity against three or more DIPG cultures

最有效的是:multi-HDAC inhibitor panobinostat

筛查结果如下:




(a) Heat map demonstrating DIPG cell line sensitivity to each of the 83 agents tested in a chemical screen of 14-patient derived DIPG cell cultures. The values shown are the absolute IC50 divided by the maximum dose. All drugs had a maximum dose of 10 μM except for drugs 26, 32, 40, 59 and 61, which had a maximum dose of 100 μM.
Values are shown as gradations of red to white: red, submicromolar IC50 values; white, IC50 greater than the maximum dose for that drug (i.e., 10 μM or 100 μM); pink, the range in between. Gray boxes indicate drugs not included in the screen for that cell line. Numbers corresponding to the drug names in the key below the heat map are listed above, and culture IDs are listed at right. The histone status of each culture used in the screen is indicated by green (wild type, WT), yellow (H3.3K27M, H3F3A-K27M) or blue (H3.1K27M, HIST1H3B-K27M); see also Supplementary Table 1. Recurrent 'hits' are visible as a column of red or pink.

(b) Dose-response curves of patient-derived DIPG lines (SU-DIPG-IV, SU-DIPG-VI, SU-DIPG-XIII, JHH-DIPG1 or SF7761 (ref. 3)) treated with the indicated drugs (x-axis) at 0.001, 0.01, 0.1, 1 or 10 μM or with 0.1% DMSO (vehicle control). n = 3 wells per condition. Cell viabilities were assessed at 72 h. Data are expressed relative to control. A pediatric cortical glioblastoma cell line (SU-pcGBM-2; histone WT) was treated in parallel for comparison in a subset. Data are shown as mean ± s.d.

(c) Panobinostat time course: DIPG cells were treated with panobinostat at the indicated concentrations (25–500 nM) or with control. n = 4 wells per condition. Cell viabilities were assessed at 0, 24, 48 and 72 h after treatment. Data are shown as mean ± s.d. **P < 0.01, ***P < 0.001; two-tailed t-test; results are shown for the lowest concentration that revealed a significant difference at 48 or 72 h.




筛查完了还需要反复实验解释得到的最有效的multi-HDAC inhibitor panobinostat 的效果的原理:

Expression of proliferation-associated genes MKI67 and CCND1 in DIPG cells decreased with time after panobinostat exposure


short hairpin RNA (shRNA)-mediated knockdown of HDAC1 or HDAC2 in the DIPG cells decreased cell viability


Western blot analyses of cells expressing the H3.3K27M mutation demonstrated a dose-dependent increase in H3 acetylation and H3K27 trimethylation following panobinostat treatment


最后说明:suggesting that the drug produced partial rescue of the H3K27M-induced global hypotrimethylation phenotype.

但是这个号称最有效的药物其实也是会被耐受的:
Highlighting the need for effective combination therapies, DIPG cells that survived chronic panobinostat exposure demonstrated resistance when re-challenged with the drug
所以作者认为应该进行联合治疗。
就跟前人工作比较一下:
首先前人发现;A recent, elegant study demonstrated utility of the histone demethylase inhibitor GSK-J4 for treating DIPG
那么我们就试验一下呗;
GSK-J4 decreased cell viability in H3K27M DIPG cell cultures
Panobinostat synergized with GSK-J4 in H3.3K27M mutant DIPG cells


哦,忘记介绍一个背景知识了:
The finding that the leading DIPG therapeutic candidate is an epigenetic modifying agent is congruent with the discovery that the majority (~80%) of DIPG tumors harbor K27M mutations in the histone H3 genes HIST1H3B or H3F3A






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