ALK与IGF的关系

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肺癌的研究揭示了新的药物组合目标
范德比尔特肺癌患者的不同类型的治疗方法寻常的反应刺激了该研究表明肺癌患者与特定的基因的改变可能与联合治疗是针对两种不同的癌症通路中受益。
工作人员报告
纳什维尔
2014年9月10日
范德比尔特肺癌患者的不同类型的治疗方法寻常的反应刺激了该研究表明肺癌患者与特定的基因的改变可能与联合治疗是针对两种不同的癌症通路中受益。

该研究由恭Lovly，医学博士，医学助理教授及癌症生物学，在网上本周发表在自然医学。

这项工作是基于一个耐人寻味的临床观察女性患者，晚期肺癌谁了一种单克隆抗体靶向胰岛素样生长因子受体（IGF-1R）意外的反应。IGF-1R帮助癌细胞生存和逃避的抗癌疗法。

值得注意的是，病人留在IGF-1R治疗了17个月 - 远高于对临床试验的任何其他病人更长的时间。范德比尔特研究人员的带领下Lovly，产生了兴趣，为什么这个病人的肿瘤反应的实验治疗的那么厉害。研究人员决定测试的基因突变，并发现一个意想不到的结果 - 患者的肿瘤呈阳性的ALK基因融合。只有约5％的肺癌患者在他们的肿瘤这个基因融合。

肺癌“ALK激酶基因融合病人入选的IGF-1R的研究后发现的。因此，没有理由认为提前与ALK阳性的肺癌患者将受益于这项实验疗法，因为肺癌ALK基因融合甚至都没有被发现，当试验最初的设想，“Lovly说。

“由于该患者的IGF-1R这样一个戏剧性的和意外的反应导向治疗，后来注意到有ALK基因融合在她的肿瘤，我们就成了兴趣了解ALK和IGF-1R尝试之间潜在的相互作用解释这个病人的IGF-1R抑制剂特殊的反应。“

有了这个新的信息，病人参加了另一项临床试验测试crizotinib，药物靶向ALK基因重组，而她的癌细胞停止前进了好多个月。

这名患者的不同形式的治疗奇怪的反应引发了一个新的研究路线，以识别和解释生物机制在起作用。Lovly和从在美国，德国和澳大利亚医学中心同事测试的IGF-1R抑制剂单独或与ALK抑制剂的组合疗法以阻止ALK阳性肺癌的生长，并克服对ALK抑制剂治疗获得性抗性的能力。

工作中的细胞系，小鼠模型和患者的肺肿瘤细胞，他们测试了两种类型的药物，发现该组合治疗增强减慢ALK阳性肺癌细胞生长的能力。他们发现在细胞相似的结果，从ALK +淋巴瘤，不同形式的癌症窝藏同一肿瘤基因的改变。

“当组合使用时，IGF-1R抑制剂和ALK抑制剂似乎协同工作来干扰细胞生长在ALK阳性肺癌细胞”，Lovly所述。

“我们需要更好的工具来对待像肺癌疾病，传统上一直抵抗治疗，越来越多，我们发现，联合治疗可能是必要的，以改善我们病患的预后。这种新的组合疗法的活性是令人鼓舞的。“

Lovly说，这项研究还强调，需要进一步评估“异常反应” - 谁拥有不同的治疗方案更好或更坏的反应比最初预计的患者。

“这种类型的分析，因为这里使用的，将有助于我们在移动领域的推进，”Lovly说。

参与研究的其他范德比尔特调查包括威廉报，医学博士，哲学博士，陈海蒂博士，英俊燕，硕士，西安Chen博士，彭城路，MS，海陵金，MS，莫妮卡红布鲁尔博士，青果王，博士，赵忠明博士和Leora霍恩博士

这项研究的其他合作者包括科学家和医师从德国科隆大学; Sloan Kettering纪念癌症中心，纽约; Dana-Farber癌症研究所，波士顿; 彼得·麦卡勒姆癌症研究中心和澳大利亚墨尔本大学。

支持这项研究包括来自美国国家癌症研究所，美国国立卫生研究院的一个部门提供资金。

原文如下：
Lung cancer study reveals new drug combination targets
A Vanderbilt lung cancer patient’s exceptional response to different types of therapies spurred research that suggests lung cancer patients with specific gene alterations may benefit from combination therapy that targets two different cancer pathways.
STAFF REPORTS
NASHVILLE
SEP 10, 2014
A Vanderbilt lung cancer patient’s exceptional response to different types of therapies spurred research that suggests lung cancer patients with specific gene alterations may benefit from combination therapy that targets two different cancer pathways.

The study, led by Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, was published online this week in Nature Medicine.

The work was based on an intriguing clinical observation of a female patient with advanced lung cancer who had an unexpected response to a monoclonal antibody that targets the insulin-like growth factor receptor (IGF-1R). IGF-1R helps cancer cells survive and evade anti-cancer therapies.

Remarkably, the patient remained on the IGF-1R therapy for 17 months - far longer than any other patient on the clinical trial. The Vanderbilt researchers, led by Lovly, became interested in why this particular patient’s tumor responded to the experimental therapy so dramatically. Investigators decided to test for gene mutations and found an unexpected result - the patient’s tumor was positive for an ALK gene fusion. Only about 5 percent of lung cancer patients have this gene fusion in their tumor.

“ALK kinase gene fusions in lung cancer were discovered after the patient enrolled on the IGF-1R study. So there was no reason to think in advance that a patient with ALK+ lung cancer would benefit from this experimental therapy, since ALK gene fusions in lung cancer had not even been discovered when the trial was initially conceived,” Lovly said.

“Since this patient had such a dramatic and unexpected response to the IGF-1R directed therapy, and was later noted to have an ALK gene fusion in her tumor, we became interested in understanding the potential interplay between ALK and IGF-1R to try to explain this patient’s exceptional response to the IGF-1R inhibitor.”

With this new information, the patient was enrolled in another clinical trial testing crizotinib, a drug that targets ALK rearrangements, and her cancer stopped progressing for several more months.

This patient’s surprising response to different forms of therapy sparked a new line of research to identify and explain the biological mechanisms at work. Lovly and colleagues from medical centers in the United States, Germany and Australia tested the ability of IGF-1R inhibitor therapies alone or in combination with ALK inhibitors to impede the growth of ALK+ lung cancer and to overcome acquired resistance to ALK inhibitor therapies.

Working in cell lines, mouse models and patient lung tumor cells, they tested the two types of drugs and found that the combination therapy enhanced the ability to slow down the growth of ALK+ lung cancer cells. They found similar results in cell lines from ALK+ lymphoma, a different form of cancer harboring the same tumor genetic alteration.

“When used in combination, the IGF-1R inhibitor and an ALK inhibitor appear to work cooperatively to interfere with cell growth in ALK+ lung cancer cells,” Lovly said.

“We need better tools to treat diseases like lung cancer that traditionally have been resistant to therapy, and increasingly, we are finding that combination therapies may be necessary to improve outcomes for our patients. The activity of this new combination therapy is encouraging.”

Lovly said the study also stresses the need to further evaluate the ‘outlier responders’ - patients who have much better or much worse responses to different therapeutic regimens than initially anticipated.

“This type of analysis, as employed here, will help us move the field forward,” said Lovly.

Other Vanderbilt investigators participating in the study include William Pao, M.D., Ph.D., Heidi Chen, Ph.D., Yingjun Yan, M.S., Xi Chen, Ph.D., Pengcheng Lu, M.S., Hailing Jin, M.S., Monica Red-Brewer, Ph.D., Qingguo Wang, Ph.D., Zhongming Zhao, Ph.D., and Leora Horn, M.D.

Other collaborators on the study include scientists and physicians from the University of Cologne, Germany; Memorial Sloan Kettering Cancer Center, New York; Dana-Farber Cancer Institute, Boston; Peter MacCallum Cancer Center and University of Melbourne, Australia.

Support for the study includes funding from the National Cancer Institute, a division of the National Institutes of Health.