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Nature:间歇性给予威罗菲尼片治疗黑素瘤可推迟耐药性的产生

2013-02-07 shumufeng Nature

美国加利弗尼亚州和瑞士的研究者发现黑素瘤不但可对威罗菲尼片产生抗性,同时也易成瘾,这一发现可能对晚期黑素瘤患者产生重大影响。来自加州大学(UCSF)、加州埃默里维尔的诺华生物医学研究所,以及瑞士苏黎世大学的研究小组发现,黑素瘤细胞对威罗菲尼片产生耐性的机制,同样使之对该药产生依赖性(药物成瘾)。其结果是,黑素瘤细胞无可救药地利用威罗菲尼片刺激自身的快速生长,直到发展为致死性、耐药性肿瘤。 这项研

美国加利弗尼亚州和瑞士的研究者发现黑素瘤不但可对威罗菲尼片产生抗性,同时也易成瘾,这一发现可能对晚期黑素瘤患者产生重大影响。来自加州大学(UCSF)、加州埃默里维尔的诺华生物医学研究所,以及瑞士苏黎世大学的研究小组发现,黑素瘤细胞对威罗菲尼片产生耐性的机制,同样使之对该药产生依赖性(药物成瘾)。其结果是,黑素瘤细胞无可救药地利用威罗菲尼片刺激自身的快速生长,直到发展为致死性、耐药性肿瘤。

这项研究发表于本周的Nature杂志,它这样写道:“研究小组的基础研究发现,在校正药物剂量并引入间歇性治疗方案后,黑素瘤小鼠模型的生存时间得到延长。”该研究的牵头研究员, Martin McMahon博士说:“很显然,威罗菲尼片间歇性给药方案会延长耐药性黑素瘤小鼠的生存期,”他是 UCSF Helen Diller Family 综合肿瘤中心肿瘤生物学的 Efim Guzik 杰出教授。因此,利用相似的途径也许可以延长这种药物的有效作用期——当然,这一想法的可行性还有待于临床试验的检验。

研究通过公私合作的方式展开,本文第一作者Meghna Das Thakur是该研究的首席研究员,他在诺华公司从事博士后研究,由 UCSF 的 McMahon 教授给予指导。 McMahon 得到了黑素瘤研究联盟、国家癌症研究所,以及UCSF Helen Diller 家族综合癌症中心(全国顶尖的癌症研究和临床服务中心)的支持,后者是圣弗郎西斯科湾区唯一一所综合癌症中心。

黑素瘤:一种致死性皮肤癌

黑素瘤是一种最具侵犯性的皮肤癌,仅2012年,美国就有76,250例患者新诊为黑素瘤。根据国家癌症研究所的数据,去年有9180例患者死于该疾病。一如其他类型的肿瘤,体内正常细胞突变的积累和潜在的变异导致了它们异常增殖和转移,黑素瘤就出现了。黑素瘤中最常见的突变基因为BRAF,有超过一半的黑素瘤患者携带有BRAF突变。

2011年,基于临床试验显示的积极的生存期数据,美国食品药物监督管理局 (FDA) 批准威罗菲尼片用于BRAF突变型晚期黑素瘤患者。然而,这种药物的获益不会永久性持续。患者的肿瘤开始消退,但大部分服用威罗菲尼的患者会遭受疾病复发并最终导致致死性、耐药性黑素瘤。

实验室中,研究人员观察到小鼠模型中出现了同样的情形。当接种黑素瘤细胞的小鼠接触威罗菲尼后,肿瘤灶开始消退,但最终小鼠对该药物的应答将终止,耐药性肿瘤将会卷土重来。

如何应对耐药性机制

利用实验室模型, UCSF 和 NIBR 研究小组揭示了威罗菲尼的耐药性机制。他们发现当黑素瘤细胞还对威罗菲尼保持应答时,抗性就已经开始产生了,其途径是表达更多的BRAF蛋白,这种蛋白恰恰是该药物自身的靶点。

于是间歇性给药的理念便应运而生。如果肿瘤开始对威罗菲尼的抗肿瘤性能产生抗性,那么也就意味着黑素瘤已经对该药产生了依赖性,Das Thakur 及其同事说,他们准确地观察到,当停止使用威罗菲尼后,耐药性肿瘤便可消退。

研究小组观察到当对复发性耐药性肿瘤小鼠模型停止给予威罗菲尼后,肿瘤再次消退。而且,持续给予威罗菲尼药物治疗的小鼠在100内全部死去,但以“药物窗口”模式有规律地给予威罗菲尼治疗的小鼠生存期全部超过100天。

“对于BRAF突变型黑素瘤患者亚群来说,威罗菲尼无疑是一种革命性的药物,但药物抵抗性的产生对其长期效果产生了不良影响,”McMahon说道,他是UCSF Helen Diller 家族综合肿瘤医院肿瘤生物学的 Efim Guzik 杰出教授。“通过寻找威罗菲尼耐药性产生的机制,我们发现了延长药物应答期的方法,即间歇性给药策略。”

doi:10.1038/nature11814
PMC:
PMID:

Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance

Meghna Das Thakur, Fernando Salangsang, Allison S. Landman, William R. Sellers, Nancy K. Pryer, Mitchell P. Levesque, Reinhard Dummer, Martin McMahon & Darrin D. Stuart

Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥50% of tumours expressing the BRAF(V600E) oncoprotein1, 2. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance3, 4. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy5. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)MEKERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.

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    2016-01-26 doctording1

    这篇文章有一定深度

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=59716, encodeId=1af859e1695, content=这篇文章有一定深度, beContent=null, objectType=article, channel=null, level=null, likeNumber=163, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59121683644, createdName=doctording1, createdTime=Tue Jan 26 16:46:00 CST 2016, time=2016-01-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=59717, encodeId=e8b159e17b8, content=是一篇不错的文章, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59121683644, createdName=doctording1, createdTime=Tue Jan 26 16:46:00 CST 2016, time=2016-01-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1879432, encodeId=60db18e94329e, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Wed May 29 13:33:00 CST 2013, time=2013-05-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1954989, encodeId=d58c195498919, content=<a href='/topic/show?id=732f9e265d7' target=_blank style='color:#2F92EE;'>#间歇性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97265, encryptionId=732f9e265d7, topicName=间歇性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55683, createdName=仁医06, createdTime=Thu Dec 26 16:33:00 CST 2013, time=2013-12-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1744070, encodeId=e1551e4407092, content=<a href='/topic/show?id=568a45016d1' target=_blank style='color:#2F92EE;'>#威罗菲尼#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=89, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=45016, encryptionId=568a45016d1, topicName=威罗菲尼)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=06fc35265945, createdName=qjddjq, createdTime=Tue Jan 14 16:33:00 CST 2014, time=2014-01-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1479400, encodeId=1a1314e9400e5, content=<a href='/topic/show?id=4a571033209b' target=_blank style='color:#2F92EE;'>#黑素瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=67, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=103320, encryptionId=4a571033209b, topicName=黑素瘤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4d4d7523220, createdName=yuhaisheng_ibp_32061713, createdTime=Sat Feb 09 05:33:00 CST 2013, time=2013-02-09, status=1, ipAttribution=)]
    2016-01-26 doctording1

    是一篇不错的文章

    0

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    2013-05-29 liye789132251
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