新药可以阻止肿瘤生长

资讯来源：Greg Glasgow

编辑翻译：菁菁

译文校对：奇奇

本文献于2021年4月首次发表在最新的《美国国家科学院院刊》（Proceedings of the National Academy of Sciences）。文献介绍了可用于治疗黑色素瘤等癌症的新药。

得益于科罗拉多大学癌症中心的研究人员所做的工作，癌症医生可能很快就会拥有一种用于治疗黑色素瘤和其他类型癌症的新武器。

在上个月发表在PNAS期刊上的一篇论文中，CU癌症中心的成员、医学博士Mayumi Fujita等人详细介绍了他们关于NLRP3的研究。NLRP3是一种细胞内复合物，被发现参与黑色素瘤介导的炎症，导致肿瘤的生长和进展。研究人员发现，通过抑制NLRP3可以减少炎症，并抑制炎症引发的肿瘤扩散。

具体而言，NLRP3通过诱导白细胞介素-1-β的成熟和释放来促发炎症。白细胞介素-1-β是引起炎症的细胞因子，是应对感染进行正常免疫反应的一部分。但是，在癌症中，炎症会导致肿瘤生长和扩散。

研究人员之一、医学博士Marchetti说：“NLRP3是一个较大家族的成员，该家族参与对危险信号的感知。它是一种监视细胞胞间区的受体，能够寻找危险分子或病原体。当NLRP3识别这些信号时，它会导致caspase-1的活化。caspase-1是一种蛋白质，与白介素-1-β转变为生物活性形式的过程和结果相关，能够引起强烈的炎症反应。我们发现，在黑色素瘤中，该过程失调，导致肿瘤生长。”

这一研究中的口服NLRP3抑制剂（Dapansutrile）在临床试验中已显示出能够有效治疗痛风和心脏病的功效，目前也在COVID-19相关研究中进行测试。CU癌症研究人员现在正试图验证这种NLRP3抑制剂是否可以成功用于对检查点抑制剂有耐药性的黑色素瘤患者中。

Marchetti说：“检查点抑制剂增强了免疫系统杀死肿瘤的功效，但有时肿瘤会对这一疗法产生抗药性。目前癌症研究领域中，一个重要方向就是开发可以与检查点抑制剂结合使用的疗法，以提高其疗效。”

CU癌症中心的研究人员提出假设，认为NLRP3抑制剂是其中一种疗法，并据此研究该药物对黑素瘤、乳腺癌和胰腺癌的作用。

除了改善免疫反应，NLRP3抑制剂还可以帮助减少检查点抑制剂的副作用。马尔凯蒂说，这项研究对仅对检查点抑制剂无反应的黑色素瘤患者可能会有很大的不同。

他说：“这是一个协作项目，涉及到大学的许多成员，对此我们感到非常兴奋。” 这个项目很重要，因为它进一步表明NLRP3介导的炎症在黑色素瘤的进展中起着关键作用，并且为改善患者护理提供了新的策略。” 

英语原文

A Drug That Can Stop Tumors From Growing

Cancer doctors may soon have a new tool for treating melanoma and other types of cancer, thanks to work being done by researchers at the University of Colorado Cancer Center.

In a paper published in the journal PNAS last month, CU Cancer Center members Mayumi Fujita, MD, Ph.D., Angelo D'Alessandro, Ph.D., Morkos Henen, Ph.D., MS, Beat Vogeli, Ph.D., Eric Pietras, Ph.D., James DeGregori, Ph.D., Carlo Marchetti, Ph.D., and Charles Dinarello, MD, along with Isak Tengesdal, MS, a graduate student in the Division of Infectious Diseases at the University of Colorado School of Medicine, detail their work on NLRP3, an intracellular complex that has been found to participate in melanoma-mediated inflammation, leading to tumor growth and progression. By inhibiting NLRP3, the researchers found, they can reduce inflammation and the resultant tumor expansion.

Specifically, NLRP3 promotes inflammation by inducing the maturation and release of interleukin-1-beta, a cytokine that causes inflammation as part of the normal immune response to infection. In cancer, however, inflammation can cause tumors to grow and spread.

"NLRP3 is a member of a larger family that is involved in sensing danger signals," Marchetti says. "It is a receptor that surveils the intercellular compartment of a cell, looking for danger molecules or pathogens. When NLRP3 recognizes these signals, it leads to the activation of caspase-1, a protein involved in the processing and maturation of interleukin-1-beta into its biological active form, causing an intense inflammatory response. We found that in melanoma, this process is dysregulated, resulting in tumor growth."

The oral NLRP3 inhibitor used in their study (Dapansutrile) has already shown to be effective in clinical trials to treat gout and heart disease, and it is currently being tested in COVID-19 as well. The CU cancer researchers are now trying to find out if this NLRP3 inhibitor can be successfully used in melanoma patients who are resistant to checkpoint inhibitors.

"Checkpoint inhibitors increase the efficacy of the immune system to kill tumors, but sometimes tumors become resistant to this treatment," Marchetti says. "A big part of cancer research now is to find therapies that can be combined with checkpoint inhibitors to improve their efficacy."

With the hypothesis that an NLRP3 inhibitor is one of those therapies, CU Cancer Center researchers are studying the drug's effects on melanoma, as well as breast cancer and pancreatic cancer. In addition to improving the immune response, the NLRP3 inhibitor can also help reduce the side effects of checkpoint inhibitors. Marchetti says this research can make a big difference for melanoma patients who don't respond to checkpoint inhibitors alone.

"This was a very collaborative project that involved a lot of members of the university, and we are very excited about it," he says. This project is important because it further shows that NLRP3-mediated inflammation plays a critical role in the progression of melanoma, and it opens new strategies to improve patient care."

More information: Isak W. Tengesdal et al, Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion, Proceedings of the National Academy of Sciences (2021). 

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