基因组测试的链接和异常与罕见的基因突变在膀胱癌-达纳法伯癌症研究所的药物反应

一个在I期临床试验的晚期膀胱癌患者14个月的联合靶向药物依维莫司和帕唑帕尼已经完全反应，科学家报告由达纳-法伯癌症研究所的研究员，和他的肿瘤基因组分析显示两个变化可能导致了这一特殊的反应。

这些信息可以帮助识别癌症患者可能对依维莫司，根据该报告发表在癌症发现美国癌症研究协会杂志。

“学习优秀者可以帮助我们理解为什么有些肿瘤对某些抗癌药物高度敏感的具体原因，说：”Nikhil Wagle，MD，达纳法伯癌症研究所，该报告的第一作者。“我们可以利用这些信息来鉴别肿瘤的基因变异，与那些在特殊反应中发现的基因改变，并用这些相同的药物治疗。”

特殊的反应是罕见的癌症患者的癌症是非常敏感的药物，并有长期的反应，治疗。

“我们进行了一项I期临床试验，两抗癌剂的mTOR抑制剂依维莫司的疗效和帕唑帕尼，另一种药物，被批准用于治疗肾脏癌和肉瘤和我们的一个病人在他的膀胱癌历时14个月的完全缓解，”Wagle，谁也对麻省理工和哈佛学院会员。一个完整的反应，药物是当所有迹象的肿瘤消失。

“我们进行了全外显子测序病人的肿瘤，又给我们惊喜，我们发现了基因的两个突变mTOR，这是依维莫司的目标，”Wagle。这种基因所产生的蛋白质在许多细胞功能中起着作用，并且在一些癌症中被发现突变。mTOR抑制剂依维莫司已被批准用于治疗某些癌症，包括乳腺癌和肾。

在这一阶段，我试验，研究人员招募了九名晚期实体瘤患者，其中包括五例膀胱癌患者，其疾病进展尽管标准疗法治疗。患者接受13个周期的依维莫司和帕唑帕尼。

其中五例膀胱癌患者有一个完整的反应，作为评估的成像，历时14个月。为了理解为什么他的肿瘤反应显着，研究者完成了他的肿瘤基因组的编码区，其中包括约25000个基因，并确定了2个突变mTOR。

The two mutations, mTOR E2419K and mTOR E2014K, had never been identified in humans, according to Wagle, although one of the mutations had previously been well studied by scientists in yeast and in human cell lines。

Wagle and colleagues conducted further laboratory studies to understand the nature of the two mutations, and found that they activated the mTOR-mediated cell signaling pathway, leading to sustained cancer cell proliferation。These mutations likely rendered the patient’s cancer dependent on the mTOR pathway to survive, which is the likely reason the cancer became exquisitely sensitive to the mTOR inhibitor everolimus, explained Wagle。

“Results of our study suggest that we should make a catalogue of activating genome alterations in the mTOR pathway,” said Wagle。“Patients with tumors that harbor these alterations might be particularly suitable for treatment with drugs like everolimus and other mTOR inhibitors。

“This is yet another example of how therapies targeted toward the genetic features of a tumor can be highly effective, and our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients,” said Wagle。“There are many more patients out there with extraordinary responses to a variety of anticancer therapies, and it will be of great scientific and clinical value to study them.”

Senior authors of the report are Levi Garraway, MD, PhD, of Dana-Farber and Senior Associate Member at the Broad, and Jonathan Rosenberg, MD, of Memorial Sloan-Kettering Cancer Center。Rosenberg was at Dana-Farber when the project began。

The research was funded by the Next Generation Fund at the Broad Institute of MIT and Harvard, the National Human Genome Research Institute, GlaxoSmithKline, and Novartis。Wagle is an equity holder and a consultant to Foundation Medicine。
 

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