抗排斥药物雷帕霉素在肝癌中显示出前景

StephenW

Anti-rejection drug rapamycin shows promise in liver cancer
by Arlene Weintraub | Feb 1, 2019 12:26pm
Liver tissue on scaffold
More than 20% of liver cancers have mutations in the β-catenin gene that may make them responsive to anti-rejection drug rapamycin, Pitt researchers reported. (H Rashidi 2018)


Scientists at the University of Pittsburgh School of Medicine were studying the cells that surround the liver’s central vein when they made a serendipitous discovery. Cells with a mutation in a gene called β-catenin also made high levels of the mTOR protein—a fault that they believe could promote the development of cancer.

Since there are already mTOR inhibitors on the market, including anti-rejection drug rapamycin, they wanted to dig deeper to learn whether those drugs could be repurposed in liver cancer. So they created a mouse model of liver cancer with mutations in the β-catenin and MET genes, creating animals with tumors that are similar to more than 20% of liver cancers in people.

When they fed the mice rapamycin, the tumors shrunk. When they added a MET inhibitor, the cancers almost disappeared completely, the Pitt researchers reported in the journal Cell Metabolism.



Inhibiting mTOR has been tried before in liver cancer but with little success. A 2016 trial in 525 patients with the disease, for example, found little difference in survival between patients given mTOR inhibitor sirolimus after liver transplantation versus patients who received a different sort of anti-rejection drug. The Pitt researchers believe their results argue for a more refined approach, targeting mTOR inhibitors to patients whose liver tumors have both β-catenin mutations and an addiction to the mTOR protein.

By studying the mouse models of liver cancer that they created, the scientists discovered that β-catenin uses an enzyme called glutamine synthase to activate mTOR. “Activating mTOR kicks up the protein-making factories in these cells, giving them the resources to divide and grow,” said senior author Satdarshan Monga, M.D., professor of pathology and director of the Pittsburgh Liver Research Center at Pitt, in a statement.


Rapamycin analogs are already approved and on the market to treat a range of cancers, including renal cell carcinoma and HER2-negative breast cancer. The crowding of the market for mTOR inhibitors in oncology may have prompted AstraZeneca’s recent decision to drop its midstage candidate vistusertib, in spite of promising data in a range of cancers.

At the very least, Pitt’s Monga believes his team’s findings argue for an approach whereby liver cancer patients who undergo transplants are given rapamycin as the preferred anti-rejection medicine over other choices.

“Current liver cancer therapies increase the likelihood of survival only by 3 or 4 months, so taking a precision medicine approach to identify the right patient could allow us to repurpose existing drugs to improve treatment success,” he said.

The next step for the Pitt researchers is to plan a clinical trial testing rapamycin as a treatment for liver cancer and as a way to prevent recurrences in patients who have received liver transplants.

StephenW

抗排斥药物雷帕霉素在肝癌中显示出前景
作者：Arlene Weintraub | 2019年2月1日下午12:26
肝组织在脚手架上
皮特研究人员报告说，超过20％的肝癌有β-catenin基因突变，这可能使它们对抗排斥药物雷帕霉素有反应。 （H Rashidi 2018）


匹兹堡大学医学院的科学家正在研究肝脏中央静脉周围的细胞，这些细胞是偶然发现的。在一种叫做β-连环蛋白的基因中发生突变的细胞也会产生高水平的mTOR蛋白 - 这是他们认为可能促进癌症发展的错误。

由于市场上已经存在mTOR抑制剂，包括抗排斥药物雷帕霉素，他们想深入了解这些药物是否可以在肝癌中重新利用。因此，他们创建了一种肝癌小鼠模型，其中β-连环蛋白和MET基因发生突变，从而产生的肿瘤与人类中超过20％的肝癌相似。

当他们给老鼠喂食雷帕霉素时，肿瘤缩小了。皮特研究人员在“细胞代谢”杂志上报告说，当他们添加MET抑制剂时，癌症几乎完全消失。



之前在肝癌中已经尝试过抑制mTOR，但收效甚微。例如，在525名患有该疾病的患者中进行的2016年试验发现，肝移植后给予mTOR抑制剂西罗莫司的患者与接受不同类型抗排斥药物的患者的生存率差异不大。皮特研究人员认为，他们的结果主张采用更精细的方法，将mTOR抑制剂用于肝脏肿瘤同时具有β-catenin突变和mTOR蛋白成瘾的患者。

通过研究他们创造的肝癌小鼠模型，科学家发现β-连环蛋白使用一种叫做谷氨酰胺合酶的酶来激活mTOR。 “激活mTOR开辟这些细胞中的蛋白质制造工厂，为他们提供分裂和成长的资源，”资深作者，匹兹堡肝病研究中心主任Satdarshan Monga博士说。


雷帕霉素类似物已被批准并在市场上用于治疗一系列癌症，包括肾细胞癌和HER2阴性乳腺癌。 mTOR抑制剂在肿瘤学市场上的拥挤可能促使阿斯利康最近决定放弃其中期候选人vistusertib，尽管有一系列癌症的数据很有希望。

至少，Pitt的Monga认为他的团队的研究结果证明了一种方法，即接受移植的肝癌患者被雷帕霉素作为首选的抗排斥药物而不是其他选择。

“目前的肝癌治疗只增加了3或4个月的生存可能性，因此采用精确医学方法确定合适的患者可以让我们重新利用现有药物来改善治疗成功率，”他说。

Pitt研究人员的下一步是计划一项临床试验，测试雷帕霉素作为肝癌的治疗方法，并作为预防接受肝脏移植的患者复发的一种方法。