Sci Transl Med:重大进展!王红阳院士团队揭示胆管癌精准治疗新策略

2020-09-25 椰子 iNature

胆管癌恶性程度高,进展快,临床就诊时多属晚期,且多已复发转移,可手术率低;常规放化疗对胆管癌的疗效非常有限,在其他肿瘤中已显示明确疗效的靶向治疗、免疫治疗等手段在胆管癌中的尝试也鲜见成功例子。

胆管癌恶性程度高,进展快,临床就诊时多属晚期,且多已复发转移,可手术率低;常规放化疗对胆管癌的疗效非常有限,在其他肿瘤中已显示明确疗效的靶向治疗、免疫治疗等手段在胆管癌中的尝试也鲜见成功例子。东方肝胆外科医院国家肝癌科学中心王红阳院士课题组一直致力于解决这一极具挑战的临床科学问题。

2020年9月23日,美国《科学》杂志子刊《科学-转化医学》(Science Translational Medicine)在线发表了由王红阳院士课题组完成的题为“PTEN status determines the chemosensitivity toproteasome inhibition in cholangiocarcinoma”的重磅论文。该论文揭示:近40%的胆管细胞癌存在重要的抑癌基因PTEN的缺失,该突变使蛋白酶体活性明显升高,直接影响肿瘤细胞的恶性行为。经系列筛选和临床研究发现:应用多发性骨髓瘤治疗药物Bortezomib可显着抑制这类胆管癌细胞的生长;有PTEN缺失突变的胆管癌病人经Bortezomib治疗后肝脏原发肿瘤和肺转移灶显着减小,甚至消失,并伴随肿瘤标志物CA19-9趋向正常。该项工作发现了抑癌基因PTEN对蛋白酶体活性的调节作用,明确了其信号转导途径,并据此提出了胆管癌精准靶向诊疗的新策略,具有重要的临床意义,也是转化医学研究的精典范例。

总之,该项工作发现了抑癌基因PTEN对蛋白酶体活性的调节作用,明确了其信号转导途径,并据此提出了胆管癌精准靶向诊疗的新策略,具有重要的临床意义,也是转化医学研究的精典范例。

胆管癌(cholangiocarcinoma)是具有极高恶性程度的肿瘤,其发生位置遍布于毛细胆管至胆总管。按发生部位不同,可分为肝内胆管细胞癌、肝门部胆管癌和远端胆管癌,但都起源于胆管上皮细胞。胆管细胞癌是仅次于肝细胞癌的恶性肿瘤,近40年来其发病率显着上升。胆管细胞癌发病隐匿,发现时都属晚期,可根治手术率低,且复发转移率极高。不同于肝细胞癌,近10年胆细胞管癌的诊断和治疗未见明显突破,病人治疗后预后差,5年生存率不足5%.。

王红阳院士课题组首先应用靶向深度测序筛选到在肝内胆管细胞癌中存在抑癌基因PTEN的多种失活突变,突变病例比例接近40%;这种特征性突变在肝门部胆管癌和远端胆管癌也得到了验证。对下游信号通路的芯片技术结合分子生物学实验分析显示PTEN失活突变后下游蛋白酶体活性显着升高。应用蛋白酶体抑制剂Bortezomib可逆转PTEN失活突变的肿瘤细胞的恶性表型。

课题组发现:相比PTEN野生型细胞,PTEN缺失型细胞具有更高的蛋白合成速率和更高的蛋白酶体活性,当应用蛋白酶体抑制剂时大量蛋白发生聚集,肿瘤细胞因蛋白毒性应激而死亡。课题组进一步发现存在PTEN-PI3K-AKT-FOXO1信号轴,该信号轴调节可负向调控蛋白酶体组分基因转录的转录因子BACH1和MAFF的转录表达,实现对蛋白酶体活性的调控。

该项工作的重要意义在于:可通过检测PTEN的突变情况,对胆管癌病人进行分型;对存在PTEN突变的患者,给予Bortezomib等蛋白酶体抑制剂治疗,显示出明显的治疗效果,有望延长患者生存期。由于接近40%的胆管癌存在PTEN突变,且Bortezomib在临床应用于多发性骨髓瘤的治疗已超过10年,药物安全性有保障;而近期国内多个厂家的Bortezomib制剂已上市,因此这种精准诊疗的策略可为众多胆管癌患者带来针对性治疗和延长生存的福音。

此外,课题组还发现,在卵巢癌乳腺癌、前列腺癌、胶质瘤等恶性肿瘤中存在类似的PTEN突变和蛋白酶体活性升高的机制,课题组提出的基于PTEN突变情况的胆管癌精准靶向治疗可望推广到卵巢癌、前列腺癌、乳腺癌等的治疗,惠及更多患者。

东方肝胆外科医院/国家肝癌科学中心王红阳、谈冶雄、董立巍为论文共同通讯作者,研究生蒋添翼和潘宇飞、万正华博士为共同第一作者。该研究得到国家科技部重点研发项目、国家自然科学基金重点项目和上海市科委重点项目等经费的支持。

原始出处:

Tian-Yi Jiang, Yu-Fei Pan, Zheng-Hua Wan, et al.PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma.Sci Transl Med. 2020 Sep 23;12(562):eaay0152. doi: 10.1126/scitranslmed.aay0152.

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style='color:#2F92EE;'>#重大进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95780, encryptionId=f72795e80d0, topicName=重大进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b96f328, createdName=wwzzly, createdTime=Sat Nov 07 08:00:28 CST 2020, time=2020-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1657367, encodeId=d358165e367ab, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Jun 15 20:00:28 CST 2021, time=2021-06-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1748805, encodeId=9ee11e4880518, content=<a href='/topic/show?id=233a64644ca' target=_blank style='color:#2F92EE;'>#治疗新策略#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64644, encryptionId=233a64644ca, topicName=治疗新策略)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a79236200456, createdName=xiaoshitou, createdTime=Mon Nov 09 13:00:28 CST 2020, time=2020-11-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1322486, encodeId=4ae11322486c9, content=<a href='/topic/show?id=ebfce6381b8' target=_blank style='color:#2F92EE;'>#精准治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76381, encryptionId=ebfce6381b8, topicName=精准治疗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2c31495, createdName=liuyg0228, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1403527, encodeId=acb0140352e81, content=<a href='/topic/show?id=ebbde6353be' target=_blank style='color:#2F92EE;'>#精准#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76353, encryptionId=ebbde6353be, topicName=精准)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83epQX9hfEIBiaPg0e9KvLYVBCSGYydH6K6OQxBh3RaOC0TYP9HYy2v0XdHib1LFnZNU5Siak0P8oh8Aqw/132, createdBy=acd92440184, createdName=shijzhiewnjhch, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1478459, encodeId=cf5014e8459c6, content=<a href='/topic/show?id=d1a55858e70' target=_blank style='color:#2F92EE;'>#新策略#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58587, encryptionId=d1a55858e70, topicName=新策略)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da0f7431516, createdName=12498568m52暂无昵称, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1610718, encodeId=f2f71610e185f, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=)]
  4. [GetPortalCommentsPageByObjectIdResponse(id=1015910, encodeId=208e101591072, content=<a href='/topic/show?id=e37c83513be' target=_blank style='color:#2F92EE;'>#胆管癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83513, encryptionId=e37c83513be, topicName=胆管癌)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Wed Sep 08 23:36:16 CST 2021, time=2021-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1967675, encodeId=f666196e67509, content=<a href='/topic/show?id=524868346a6' target=_blank style='color:#2F92EE;'>#王红阳#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68346, encryptionId=524868346a6, topicName=王红阳)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1777154, createdName=chenhongpeng, createdTime=Tue May 11 09:00:28 CST 2021, time=2021-05-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2067519, encodeId=7a5f206e519e5, content=<a href='/topic/show?id=d0841e75535' target=_blank style='color:#2F92EE;'>#Transl#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17755, encryptionId=d0841e75535, topicName=Transl)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdqq.qlogo.cn/qqapp/101173734/363C99735735B7F4CB11D5F78F580525/100, createdBy=aab22500211, createdName=ms3025846204744509, createdTime=Wed Mar 10 04:00:28 CST 2021, time=2021-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1814538, encodeId=2b451814538d0, content=<a href='/topic/show?id=f72795e80d0' target=_blank style='color:#2F92EE;'>#重大进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95780, encryptionId=f72795e80d0, topicName=重大进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b96f328, createdName=wwzzly, createdTime=Sat Nov 07 08:00:28 CST 2020, time=2020-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1657367, encodeId=d358165e367ab, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Jun 15 20:00:28 CST 2021, time=2021-06-15, status=1, ipAttribution=), 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createdBy=2c31495, createdName=liuyg0228, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1403527, encodeId=acb0140352e81, content=<a href='/topic/show?id=ebbde6353be' target=_blank style='color:#2F92EE;'>#精准#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76353, encryptionId=ebbde6353be, topicName=精准)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83epQX9hfEIBiaPg0e9KvLYVBCSGYydH6K6OQxBh3RaOC0TYP9HYy2v0XdHib1LFnZNU5Siak0P8oh8Aqw/132, createdBy=acd92440184, createdName=shijzhiewnjhch, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1478459, encodeId=cf5014e8459c6, content=<a href='/topic/show?id=d1a55858e70' target=_blank style='color:#2F92EE;'>#新策略#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58587, encryptionId=d1a55858e70, topicName=新策略)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da0f7431516, createdName=12498568m52暂无昵称, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1610718, encodeId=f2f71610e185f, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=1015910, encodeId=208e101591072, content=<a href='/topic/show?id=e37c83513be' target=_blank style='color:#2F92EE;'>#胆管癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83513, encryptionId=e37c83513be, topicName=胆管癌)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Wed Sep 08 23:36:16 CST 2021, time=2021-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1967675, encodeId=f666196e67509, content=<a href='/topic/show?id=524868346a6' target=_blank style='color:#2F92EE;'>#王红阳#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68346, encryptionId=524868346a6, topicName=王红阳)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1777154, createdName=chenhongpeng, createdTime=Tue May 11 09:00:28 CST 2021, time=2021-05-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2067519, encodeId=7a5f206e519e5, content=<a href='/topic/show?id=d0841e75535' target=_blank style='color:#2F92EE;'>#Transl#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17755, encryptionId=d0841e75535, topicName=Transl)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdqq.qlogo.cn/qqapp/101173734/363C99735735B7F4CB11D5F78F580525/100, createdBy=aab22500211, createdName=ms3025846204744509, createdTime=Wed Mar 10 04:00:28 CST 2021, time=2021-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1814538, encodeId=2b451814538d0, content=<a href='/topic/show?id=f72795e80d0' target=_blank style='color:#2F92EE;'>#重大进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95780, encryptionId=f72795e80d0, topicName=重大进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b96f328, createdName=wwzzly, createdTime=Sat Nov 07 08:00:28 CST 2020, time=2020-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1657367, encodeId=d358165e367ab, content=<a href='/topic/show?id=3ca31e71903' target=_blank style='color:#2F92EE;'>#TRA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17719, encryptionId=3ca31e71903, topicName=TRA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=757b24868428, createdName=bsmagic9140, createdTime=Tue Jun 15 20:00:28 CST 2021, time=2021-06-15, status=1, ipAttribution=), 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createdBy=2c31495, createdName=liuyg0228, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1403527, encodeId=acb0140352e81, content=<a href='/topic/show?id=ebbde6353be' target=_blank style='color:#2F92EE;'>#精准#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76353, encryptionId=ebbde6353be, topicName=精准)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83epQX9hfEIBiaPg0e9KvLYVBCSGYydH6K6OQxBh3RaOC0TYP9HYy2v0XdHib1LFnZNU5Siak0P8oh8Aqw/132, createdBy=acd92440184, createdName=shijzhiewnjhch, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1478459, encodeId=cf5014e8459c6, content=<a href='/topic/show?id=d1a55858e70' target=_blank style='color:#2F92EE;'>#新策略#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58587, encryptionId=d1a55858e70, topicName=新策略)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da0f7431516, createdName=12498568m52暂无昵称, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1610718, encodeId=f2f71610e185f, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Sun Sep 27 05:00:28 CST 2020, time=2020-09-27, status=1, ipAttribution=)]
    2021-06-15 bsmagic9140
  6. [GetPortalCommentsPageByObjectIdResponse(id=1015910, encodeId=208e101591072, content=<a href='/topic/show?id=e37c83513be' target=_blank style='color:#2F92EE;'>#胆管癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83513, encryptionId=e37c83513be, topicName=胆管癌)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Wed Sep 08 23:36:16 CST 2021, time=2021-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1967675, encodeId=f666196e67509, content=<a href='/topic/show?id=524868346a6' target=_blank style='color:#2F92EE;'>#王红阳#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68346, encryptionId=524868346a6, 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  7. 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