A proof-of-concept trial by researchers at ETH Zurich, the University Hospitals of Basel and Zurich, and the Basel-Land Cantonal Hospital, demonstrated that treating breast cancer patients with a low, safe dose of the Na

苏黎世理工大学、巴塞尔和苏黎世大学医院以及巴塞尔土地州医院的研究人员进行的一项概念验证试验表明，用低安全剂量的Na治疗乳腺癌患者

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ATPase inhibitor digoxin significantly reduced the numbers of circulating tumor cells (CTCs) in CTC clusters. The team reported on the study results in

ATPase抑制剂地高辛显着减少CTC簇中循环肿瘤细胞（CTC）的数量。该团队报告了研究结果

Nature Medicine

自然医学

, in a paper titled, “

，在一篇题为“的论文中

Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: a proof-of-concept trial

地高辛减少转移性乳腺癌循环肿瘤细胞簇大小的概念验证试验

,” in which they concluded “… our data provide a first-in-human proof of principle that digoxin treatment leads to a partial CTC cluster dissolution, encouraging larger follow-up studies with refined Na+/K+ ATPase inhibitors and that include clinical outcome endpoints.”

，“他们在其中得出结论：“……我们的数据提供了地高辛治疗导致部分CTC簇溶解的首次人类原理证明，鼓励使用精制的Na+/K+ATPase抑制剂进行更大规模的后续研究，并包括临床结果终点。”

Certain tumor types do not remain at their point of origin but spread throughout the body and form metastases. This is because the primary tumor continuously releases cancer cells into the blood. These CTCs can join together into small clusters of up to a dozen cells and settle in other organs. There, the clusters grow into larger metastatic tumors.

某些肿瘤类型不保留在其起源点，而是扩散到全身并形成转移。这是因为原发肿瘤不断将癌细胞释放到血液中。这些CTC可以结合在一起形成多达十几个细胞的小簇，并在其他器官中定居。。

Metastatic tumors are still a major medical problem: every year, around seven million people worldwide die from them. “CTCs are living cells that are shed from both primary and metastatic lesions into the bloodstream, acting as metastatic pioneers,” the authors wrote. “The presence of CTC clusters is associated with disease progression and reduced survival in a variety of cancer types.”.

转移性肿瘤仍然是一个主要的医学问题：每年全世界约有700万人死于转移性肿瘤。。“CTC簇的存在与多种癌症类型的疾病进展和生存率降低有关。”。

One example of such a spreading tumor is breast cancer. As soon as the primary tumor forms metastases, the chances of survival decrease drastically. Tens of thousands of women worldwide still die of metastatic breast cancer. Oncologists are therefore looking for ways to weaken or destroy the clusters in order to prevent the formation of metastases.

这种扩散性肿瘤的一个例子是乳腺癌。。全世界仍有成千上万的女性死于转移性乳腺癌。因此，肿瘤学家正在寻找削弱或破坏这些簇的方法，以防止转移的形成。

“The presence of CTCs has been firmly established to be predictive of poor prognosis in patients with breast cancer,” the team noted..

该小组指出：“CTC的存在已被确定可预测乳腺癌患者的不良预后。”。。

Recent studies by the researchers and other groups found that clusters of CTCs have a larger metastatic capacity and a stronger link to poor prognosis than a single CTC. “Breast cancer metastasis depends on CTC clusters,” explained principal investigator Nicola Aceto, PhD, professor of molecular oncology at ETH Zurich.

研究人员和其他研究小组最近的研究发现，与单个CTC相比，CTC簇具有更大的转移能力和与不良预后的更强联系。苏黎世联邦理工学院分子肿瘤学教授、首席研究员尼古拉·阿克托博士解释说：“乳腺癌转移取决于CTC簇。”。

“The larger they are, the more successful they are.”.

“他们越大，就越成功。”。

The Achilles’ heel of CTC clusters are the sodium-potassium pumps (Na+/K+-ATPases) that are located in the membranes of tumor cells and are responsible for transporting sodium out of the cells and potassium into them. Digoxin blocks these ion pumps and thus suppresses the ion exchange. The cells therefore absorb more calcium from the outside of the cell membrane.

CTC簇的致命弱点是位于肿瘤细胞膜上的钠钾泵（Na+/K+-ATP酶），负责将钠从细胞中转运出来，并将钾转运到细胞中。地高辛阻断这些离子泵，从而抑制离子交换。因此，细胞从细胞膜的外部吸收更多的钙。

This weakens the cohesion of the cancer cells in the cluster, causing them to fall apart..

这削弱了集群中癌细胞的凝聚力，导致它们分裂。。

The active ingredient digoxin originally comes from the foxglove plant (Digitalis sp.) and is usually used for heart conditions such as heart failure. The ETH researchers discovered in 2019 that digoxin could also be effective in the context of breast cancer. They carried out an extensive screening in which they systematically tested more than 2,400 different substances in cell cultures to find active agents against clusters of circulating tumor cells (CTCs).

活性成分地高辛最初来自毛地黄（Digitalis sp。），通常用于治疗心力衰竭等心脏病。ETH研究人员于2019年发现，地高辛在乳腺癌的治疗中也可能有效。他们进行了广泛的筛选，系统地测试了细胞培养物中2400多种不同的物质，以寻找针对循环肿瘤细胞（CTC）簇的活性剂。

“A screen with 2,486 U.S. Food and Drug Administration-approved drugs demonstrated that Na.

“2486种美国食品和药物管理局批准的药物的屏幕显示Na。

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ATPase inhibitors, such as cardiac glycosides, effectively dissolve CTC clusters into single cells, leading to metastasis suppression in mouse models of breast cancer.”

However, digoxin alone does not eliminate the existing tumor. The agent must be administered in combination with other substances that kill existing cancer cells.

。该药物必须与其他杀死现有癌细胞的物质联合使用。

Aceto and colleagues established the prospective first-in-human proof-of-concept Phase I Digxoin Induced Dissolution of CTC Clusters (DICCT), as a therapeutic exploratory Phase I study to examine whether the Na

Aceto及其同事建立了前瞻性的第一个人类概念验证I期地高辛诱导的CTC簇溶解（DICCT），作为一项治疗性探索性I期研究，以检查Na是否

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ATPase inhibitor digoxin could disrupt CTC clusters in patients with metastatic breast cancer at dose levels that are safe and well tolerated. “The primary objective of the study was to assess the effect of digoxin on CTC cluster size in patients with metastatic breast cancer,” the team commented. “Of note, the size of CTC clusters, rather than their general abundance, best reflects cluster-dissolution properties.”.

ATPase抑制剂地高辛可以在安全且耐受性良好的剂量水平下破坏转移性乳腺癌患者的CTC簇。该团队评论道：“该研究的主要目的是评估地高辛对转移性乳腺癌患者CTC簇大小的影响。”。“值得注意的是，CTC团簇的大小，而不是它们的一般丰度，最能反映团簇的溶解特性。”。

The study included nine patients with locoregionally recurrent or metastatic breast cancer with progressive disease not amenable to treatments with curative intent, who were treated using digoxin, and nine patients with CTC clusters and matched clinical characteristics assigned to an untreated control group..

这项研究包括9名局部复发或转移性乳腺癌患者，这些患者患有进行性疾病，不适合使用地高辛进行治疗，他们使用地高辛进行治疗，以及9名CTC集群患者和匹配的临床特征分配给未经治疗的对照组。。

The study met its primary endpoint, with results showing that among patients treated with digoxin, the number of cells per cluster decreased significantly—by an average of 2.2 cells. Given that typical cluster sizes are only a handful of cells, this means a significant reduction in the risk of metastases.

该研究达到了其主要终点，结果显示，在接受地高辛治疗的患者中，每簇细胞的数量平均减少了2.2个细胞。鉴于典型的簇大小只有少数细胞，这意味着转移风险显着降低。

“… the DICCT trial successfully demonstrated that a partial dissolution of CTC clusters can be achieved through the inhibition of the Na.

“…DICCT试验成功证明，通过抑制Na可以实现CTC簇的部分溶解。

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ATPase in patients with metastatic breast cancer,” the investigators reported. “Although clinical outcome endpoints were not assessed in this proof-of-concept study, the DICCT trial provides first-in-class evidence that supports the design of novel approaches for metastasis prevention.”

转移性乳腺癌患者的ATPase，”研究人员报道。“尽管在这项概念验证研究中没有评估临床结果终点，但DICCT试验提供了一流的证据，支持设计预防转移的新方法。”

The team also noted that the effects of digoxin on a relatively low dose on cluster size were significant but mild. “We highly anticipate future studies in this context, designed for a longer treatment duration, more frequent monitoring of drug serum levels or higher dosage or using refined Na

研究小组还注意到，相对较低剂量的地高辛对簇大小的影响是显着的，但程度较轻。“我们高度期待在这方面的未来研究，旨在延长治疗时间，更频繁地监测药物血清水平或更高剂量或使用精制Na

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ATPase inhibitors with stronger cluster-dissolution activity and aimed at measuring clinical endpoints related to new metastasis development.”

ATPase抑制剂具有更强的簇溶解活性，旨在测量与新转移发展相关的临床终点。”

In the next step, the researchers want to develop new molecules based on digoxin that are even better at dissolving the CTC clusters. The ETH spin-off, Page Therapeutics is already working on this solution. Aceto also wants to expand his research to other types of cancer that spread, such as prostate, colorectal, or pancreatic cancer, as well as melanoma.

下一步，研究人员希望开发基于地高辛的新分子，这些分子甚至可以更好地溶解CTC簇。ETH的附属公司Page Therapeutics已经在开发这种解决方案。Aceto还想将他的研究扩展到其他扩散的癌症，如前列腺癌、结直肠癌或胰腺癌以及黑色素瘤。

Initial experiments in his laboratory have already begun..

他实验室的初步实验已经开始。。

News

新闻

Breast cancer

乳腺癌

Cancer cell migration

癌细胞迁移

Cancer drug discovery

癌症药物发现

Metastasis

转移

Phase I clinical trials (Clinical trial)

I期临床试验（临床试验）