针对EZH2-异常固体瘤的治疗策略
Xun Huang1, Juan Yan2, Min Zhang3
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
Cell
|September 18, 2018
概括
提高EZH2抑制剂的有效性包括针对表观基因交叉和MAPK通路. 结合疗法对EZH2异常的固体瘤有希望,改善治疗结果.
科学领域:
- 癌症学
- 表观遗传学
- 分子生物学
背景情况:
- 增强Zeste同源2 (EZH2) 突变在癌症中很常见,但EZH2抑制剂 (EZH2i) 的疗效有限,主要是在血液恶性瘤中.
- 了解抗 EZH2i 的机制对于开发有效的癌症疗法至关重要.
研究的目的:
- 研究各种癌症类型中对EZH2抑制剂耐药性的机制.
- 确定EZH2异常固体瘤的新疗法.
主要方法:
- 在具有不同EZH2i灵敏度的癌细胞系中分析全球转化后的基因组变异.
- 分析MLL1,p300/CBP复合体和基因组修饰 (H3K27me,H3K27ac) 之间的相互作用.
- 在固体瘤模型中对包括EZH2,BRD4和MAPK抑制剂在内的组合疗法的临床前测试.
主要成果:
- 通过MLL1- p300/ CBP相互作用的瘤转录编程导致H3K27me损失和H3K27ac增加,限制EZH2i反应.
- 同时抑制H3K27me和H3K27ac导致转录抑制和MAPK路径依赖.
- 在EZH2异常固体瘤的临床前模型中,EZH2和BRD4抑制剂的联合治疗或MAPK抑制的三重治疗显示出显著的疗效和耐受性.
结论:
- MLL1表达水平可以预测对EZH2向治疗的反应.
- 同时抑制表观基因交叉声和MAPK信号提供了一个有前途的精确治疗策略,用于EZH2异常的固体瘤.
- 针对EZH2,BRD4和MAPK途径的组合疗法是克服EZH2抑制剂耐药性的可行方法.
相关概念视频
Epigenetic Regulation
33.8K
Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
33.8K
Epigenetic Regulation
3.9K
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...
3.9K
Metallic Solids
20.7K
Metallic solids such as crystals of copper, aluminum, and iron are formed by metal atoms. The structure of metallic crystals is often described as a uniform distribution of atomic nuclei within a “sea” of delocalized electrons. The atoms within such a metallic solid are held together by a unique force known as metallic bonding that gives rise to many useful and varied bulk properties.
All metallic solids exhibit high thermal and electrical conductivity, metallic luster, and malleability....
All metallic solids exhibit high thermal and electrical conductivity, metallic luster, and malleability....
20.7K
Structures of Solids
17.8K
Solids in which the atoms, ions, or molecules are arranged in a definite repeating pattern are known as crystalline solids. Metals and ionic compounds typically form ordered, crystalline solids. A crystalline solid has a precise melting temperature because each atom or molecule of the same type is held in place with the same forces or energy. Amorphous solids or non-crystalline solids (or, sometimes, glasses) which lack an ordered internal structure and are randomly arranged. Substances that...
17.8K
Network Covalent Solids
16.2K
Network covalent solids contain a three-dimensional network of covalently bonded atoms as found in the crystal structures of nonmetals like diamond, graphite, silicon, and some covalent compounds, such as silicon dioxide (sand) and silicon carbide (carborundum, the abrasive on sandpaper). Many minerals have networks of covalent bonds.
To break or to melt a covalent network solid, covalent bonds must be broken. Because covalent bonds are relatively strong, covalent network solids are typically...
To break or to melt a covalent network solid, covalent bonds must be broken. Because covalent bonds are relatively strong, covalent network solids are typically...
16.2K
Molecular and Ionic Solids
20.1K
Crystalline solids are divided into four types: molecular, ionic, metallic, and covalent network based on the type of constituent units and their interparticle interactions.
Molecular Solids
Molecular crystalline solids, such as ice, sucrose (table sugar), and iodine, are solids that are composed of neutral molecules as their constituent units. These molecules are held together by weak intermolecular forces such as London dispersion forces, dipole-dipole interactions, or hydrogen bonds, which...
Molecular Solids
Molecular crystalline solids, such as ice, sucrose (table sugar), and iodine, are solids that are composed of neutral molecules as their constituent units. These molecules are held together by weak intermolecular forces such as London dispersion forces, dipole-dipole interactions, or hydrogen bonds, which...
20.1K


