數十種非腫瘤藥物可以殺死癌細胞 Dozens of non-oncology drugs can kill cancer cells

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Editor’s note:  Killing cancer cells is not a good strategy because when you try to kill them, some cancer cell survivors will be trained to be more aggressive.  That is why cancer can come back after seemingly a few years of remission.  The best thing to do is mobilize patients’s immune system to fight cancer cells.
 
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Dozens of non-oncology drugs can kill cancer cells

A study testing thousands of medicines in hundreds of cancer cell lines in the lab uncovers new tricks for many old drugs

BROAD INSTITUTE OF MIT AND HARVARD

Drugs for diabetes, inflammation, alcoholism — and even for treating arthritis in dogs — can also kill cancer cells in the lab, according to a study by scientists at the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute. The researchers systematically analyzed thousands of already developed drug compounds and found nearly 50 that have previously unrecognized anti-cancer activity. The surprising findings, which also revealed novel drug mechanisms and targets, suggest a possible way to accelerate the development of new cancer drugs or repurpose existing drugs to treat cancer.

“We thought we’d be lucky if we found even a single compound with anti-cancer properties, but we were surprised to find so many,” said Todd Golub, chief scientific officer and director of the Cancer Program at the Broad, Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber, and professor of pediatrics at Harvard Medical School.

The new work appears in the journal Nature Cancer. It is the largest study yet to employ the Broad’s Drug Repurposing Hub, a collection that currently comprises more than 6,000 existing drugs and compounds that are either FDA-approved or have been proven safe in clinical trials (at the time of the study, the Hub contained 4,518 drugs). The study also marks the first time researchers screened the entire collection of mostly non-cancer drugs for their anti-cancer capabilities.

Historically, scientists have stumbled upon new uses for a few existing medicines, such as the discovery of aspirin’s cardiovascular benefits. “We created the repurposing hub to enable researchers to make these kinds of serendipitous discoveries in a more deliberate way,” said study first author Steven Corsello, an oncologist at Dana-Farber, a member of the Golub lab, and founder of the Drug Repurposing Hub.

The researchers tested all the compounds in the Drug Repurposing Hub on 578 human cancer cell lines from the Broad’s Cancer Cell Line Encyclopedia (CCLE). Using a molecular barcoding method known as PRISM, which was developed in the Golub lab, the researchers tagged each cell line with a DNA barcode, allowing them to pool several cell lines together in each dish and more quickly conduct a larger experiment. The team then exposed each pool of barcoded cells to a single compound from the repurposing library, and measured the survival rate of the cancer cells.

They found nearly 50 non-cancer drugs — including those initially developed to lower cholesterol or reduce inflammation — that killed some cancer cells while leaving others alone.

Some of the compounds killed cancer cells in unexpected ways. “Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms,” said Corsello. Some of the four-dozen drugs he and his colleagues identified appear to act not by inhibiting a protein but by activating a protein or stabilizing a protein-protein interaction. For example, the team found that nearly a dozen non-oncology drugs killed cancer cells that express a protein called PDE3A by stabilizing the interaction between PDE3A and another protein called SLFN12 — a previously unknown mechanism for some of these drugs.

These unexpected drug mechanisms were easier to find using the study’s cell-based approach, which measures cell survival, than through traditional non-cell-based high-throughput screening methods, Corsello said.

Most of the non-oncology drugs that killed cancer cells in the study did so by interacting with a previously unrecognized molecular target. For example, the anti-inflammatory drug tepoxalin, originally developed for use in people but approved for treating osteoarthritis in dogs, killed cancer cells by hitting an unknown target in cells that overexpress the protein MDR1, which commonly drives resistance to chemotherapy drugs.

The researchers were also able to predict whether certain drugs could kill each cell line by looking at the cell line’s genomic features, such as mutations and methylation levels, which were included in the CCLE database. This suggests that these features could one day be used as biomarkers to identify patients who will most likely benefit from certain drugs. For example, the alcohol dependence drug disulfiram (Antabuse) killed cell lines carrying mutations that cause depletion of metallothionein proteins. Compounds containing vanadium, originally developed to treat diabetes, killed cancer cells that expressed the sulfate transporter SLC26A2.

“The genomic features gave us some initial hypotheses about how the drugs could be acting, which we can then take back to study in the lab,” said Corsello. “Our understanding of how these drugs kill cancer cells gives us a starting point for developing new therapies.”

The researchers hope to study the repurposing library compounds in more cancer cell lines and to grow the hub to include even more compounds that have been tested in humans. The team will also continue to analyze the trove of data from this study, which have been shared openly (https://depmap.org) with the scientific community, to better understand what’s driving the compounds’ selective activity.

“This is a great initial dataset, but certainly there will be a great benefit to expanding this approach in the future,” said Corsello.

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This collaboration involved the Broad’s Center for the Development of Therapeutics, the PRISM team, the Cancer Data Sciences team, and the labs of Todd Golub and Matthew Meyerson. The work was funded in part by SIGMA (Carlos Slim Foundation, Slim Initiative in Genomic Medicine for the Americas), the National Institutes of Health, and an anonymous donor.

Paper cited: Corsello S, et al. Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling. Nature Cancer.

數十種非腫瘤藥物可以殺死癌細胞

5000/5000Character limit: 5000根據麻省理工學院,哈佛大學和達納-法伯癌症研究所的科學家的一項研究,用於糖尿病,炎症,酒精中毒的藥物甚至用於治療犬關節炎的藥物也可以在實驗室殺死癌細胞。研究人員系統地分析了數千種已經開發的藥物化合物,發現了近50種以前無法識別的抗癌活性。令人驚訝的發現還揭示了新的藥物機制和靶標,為加速開發新的癌症藥物或重新利用現有藥物治療癌症提供了可能的方法。

“我們發現即使發現具有抗癌特性的單一化合物,我們還是很幸運的,但是我們驚訝地發現了這麼多化合物,”查爾斯·A廣泛癌症計劃的首席科學官兼主任托德·戈魯布說。 。達娜·法伯(Dana-Farber)的人類癌症遺傳學研究人員達納(Dana),哈佛醫學院的兒科學教授。

這項新工作發表在《自然癌症》雜誌上。這是迄今為止使用Broad的藥物再利用中心的最大規模的研究,該集合目前包含6,000多種已獲FDA批准或已在臨床試驗中證明是安全的現有藥物和化合物(在研究時,該中心包含4,518種藥物)。該研究還標誌著研究人員首次針對其非抗癌能力篩選了大部分非癌症藥物。

從歷史上看,科學家偶然發現了幾種現有藥物的新用途,例如發現阿司匹林的心血管益處。研究的第一作者,Golub實驗室成員,Dana-Farber的腫瘤學家,藥物再利用創始人轂。

研究人員在廣泛的癌細胞系百科全書(CCLE)的578種人類癌細胞系中對“藥物重用中心”中的所有化合物進行了測試。研究人員使用Golub實驗室開發的一種稱為PRISM的分子條形碼方法,用DNA條形碼標記每個細胞系,從而使他們可以在每個培養皿中將多個細胞系集中在一起,從而更快地進行較大的實驗。然後,研究小組將條形碼存儲庫中的每個池都暴露於重用庫中的單一化合物中,並測量了癌細胞的存活率。

他們發現了將近50種非癌症藥物-包括最初為降低膽固醇或減輕炎症而開發的藥物-殺死了一些癌細胞,而另一些則不起作用。

一些化合物以意想不到的方式殺死癌細胞。 “大多數現有的抗癌藥物都是通過阻斷蛋白質發揮作用的,但是我們發現這些化合物可以通過其他機制起作用,” Corsello說。他和他的同事們確定的四種藥物中的某些似乎不是通過抑制蛋白質而起作用,而是通過激活蛋白質或穩定蛋白質與蛋白質的相互作用。例如,研究小組發現,有近十二種非腫瘤藥物通過穩定PDE3A和另一種稱為SLFN12的蛋白質之間的相互作用而殺死了表達PDE3A的癌細胞,這是其中一些藥物以前未知的機制。

與通過傳統的非基於細胞的高通量篩選方法相比,使用這項基於細胞的方法(用於測量細胞存活率)更容易找到這些意想不到的藥物機制。

在研究中,大多數殺死癌細胞的非腫瘤藥物都是通過與先前無法識別的分子靶標相互作用而實現的。例如,最初開髮用於人類但被批准用於治療犬骨關節炎的抗炎藥替泊沙林通過擊中過表達蛋白MDR1的細胞中的未知靶標而殺死了癌細胞,該蛋白通常會驅動對化療藥物的耐藥性。

研究人員還可以通過查看CCLE數據庫中包含的基因組特徵(例如突變和甲基化水平)來預測某些藥物是否可以殺死每個細胞系。這表明這些特徵有一天可以用作生物標記,以識別最有可能從某些藥物中受益的患者。例如,酒精依賴性藥物雙硫崙(Antabuse)殺死了攜帶導致金屬硫蛋白耗盡的突變的細胞系。最初開髮用於治療糖尿病的含釩化合物殺死了表達硫酸鹽轉運蛋白SLC26A2的癌細胞。

“基因組特徵為我們提供了有關藥物作用方式的一些初步假設,然後我們可以將其帶回實驗室進行研究,” Corsello說。 “我們對這些藥物如何殺死癌細胞的理解為我們開發新療法提供了一個起點。”

研究人員希望在更多的癌細胞系中研究重新定位的文庫化合物,並使該中樞包含更多已在人體中測試的化合物。 研究小組還將繼續分析這項研究的數據,並已與科學界公開共享(https://depmap.org),以更好地了解是什麼驅動了化合物的選擇性活性。

Corsello說:“這是一個很好的初始數據集,但是將來擴展這種方法肯定會帶來很大的好處。”

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