《自然》子刊：发现治疗晚期前列腺癌的新方法

资讯作者：University of Michigan

编辑翻译：奇奇

本文献于2021年8月2日发表在国际著名期刊《自然癌症》上。文中密歇根大学罗格尔癌症中心研究发现一种名为ESK981的抑制剂对前列腺癌的治疗效果显著，并将其应用于前列腺癌的临床治疗中，这是一种有效的新免疫治疗方法。

由密歇根大学罗格尔癌症中心(University of Michigan RogelCancer Center)领导的研究人员从一个简单的线索开始：一种有望对抗转移去势抵抗性前列腺癌细胞的抑制剂。这是最具挑战性的一种前列腺癌晚期疾病，该疾病已经对激素治疗产生了耐药性。

依据线索，他们继续往下研究，以期望发现阻止免疫系统作出反应的多层细胞过程。用这种抑制剂突破它们，免疫迟钝的肿瘤就会突然变得很有活力。

医学博士Arul M. Chinnaiyan说：“免疫疗法极大地改善了某些癌症的治疗效果。但前列腺癌是典型的免疫迟钝，这意味着该疾病患者从免疫疗法中获益甚微。找到一种加速免疫反应的方法将为改善病人的预后创造巨大的机会。”他是密歇根州转化病理学中心主任和密歇根州医学病理学教授，也是本论文的资深作者。

研究人员首先筛选了167种抗前列腺癌细胞的抑制剂库。他们发现ESK981的影响最大。ESK981是一类被称为多酪氨酸激酶抑制剂的药物，旨在击中多个靶点。这意味着它的功能类似于综合疗法，能够在多个方面阻止癌症。它最初是为了检查血管生长而开发的，已经在一期临床试验中进行了测试，该药物是安全的，而且耐受性良好。

在具有转移性前列腺癌的细胞系和小鼠中，研究人员发现ESK981抑制肿瘤生长。Chinnaiyan说：“这种反应很有趣，但我们想要了解ESK981在前列腺癌细胞中的作用机制。”

他们发现了几个细胞过程正在发生。首先是一种叫做自噬的细胞死亡的作用。研究人员惊奇地发现ESK981在肿瘤细胞中是一种有效的细胞自噬抑制剂。这导致癌细胞产生了一种叫做CXCL10的蛋白质，这种蛋白质使得免疫T细胞聚集到肿瘤上。

但还需要进一步的了解。最终，他们将其追溯到PIKfyve，这是一种叫做脂激酶的蛋白质。研究人员发现ESK981直接以PIKfyve为靶点，影响代谢和细胞死亡的多个过程。

研究人员通过在细胞系和小鼠中关闭PIKfyve证实了这一点。他们看到了相同的过程：肿瘤停止生长，自噬得到控制，更多的T细胞被聚集到肿瘤中。当他们在PIKfyve基因关闭中加入免疫检查点抑制剂时，效果更加明显，肿瘤有显著地减少了。

Chinnaiyan说：“克服对免疫疗法的耐药性是前列腺癌的迫切需要。PIKfyve有望成为一个治疗靶点，特别是与免疫检查点抑制剂联合使用。这种组合有可能会扩大免疫治疗的益处，让之前对肿瘤没有反应的患者受益。”

基于这些发现，研究人员已经开始了转移去势抵抗性前列腺癌的2期临床试验，该临床中采用单独使用ESK981或者联合使用纳武单抗的免疫疗法。

英语原文

Researchers Uncover a Way to Harness the Power of Immunotherapy for Advanced Prostate Cancer

Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer—advanced disease that has become resistant to hormone-based treatment.

From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly what's considered an immune cold tumor turns red hot.

“Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes,” says Arul M.Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. Chinnaiyan is senior author of the paper published in Nature Cancer.

Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact.

ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to besafe and well-tolerated.

In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth.

“The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells,” Chinnaiyan says.

They discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor.

But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.

“Overcoming resistance to immunotherapy is an urgent need in prostate cancer. PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded,” Chinnaiyan says.

Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.

参考文献 

Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer, Nature Cancer (2021). DOI: 10.1038/s43018-021-00237-1.

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