▲近日一項研究發現了一種新的小分子化合物 “S63845”，能有效阻止至少四分之一的已知
癌症類型的生長擴散。攝：Dan Kitwood/Getty Images/Cancer Research UK
由法國最大的獨立製藥集團 Servier 旗下研究所領銜的這項研究，發現了一種新的小分子化合物 “S63845”，它能有效阻止至少四分之一的已知癌症類型的生長擴散。而 S63845 分子是通過抑制 MCL1 蛋白質的活性來達到這一「奇效」：許多類型的癌細胞都依賴於 MCL1 才得以生長，如果癌細胞不能接觸到 MCL1 就會死亡。
不過，MCL1 對於造血等人體基本功能也是至關重要的，所以不能完全抑制其活性。研究人員稱，S63845 可以把握好抑制蛋白質活性的程度，對白老鼠的實驗顯示，攝入的新分子並未損害其造血功能。
不過，MCL1 對於造血等人體基本功能也是至關重要的，所以不能完全抑制其活性。研究人員稱，S63845 可以把握好抑制蛋白質活性的程度，對白老鼠的實驗顯示，攝入的新分子並未損害其造血功能。
這項發現為患者帶來新的希望，我們認為 S63845 將會是攻克癌症核心並抑制其反抗的一種精確治療藥物。在將來的研究和開發中，它甚至有機會幹掉其他所有的癌症。
研究參與者、血液學家 Andrew Wei
這項研究或可幫助製藥企業開發新藥來有效殺滅一般癌細胞，以及開發出治療白血病、淋巴癌等血液腫瘤（非實體瘤）和肺癌、乳腺癌、黑色素瘤等實體腫瘤的不同癌症類型的新型療法。
論文通訊作者 Olivier Geneste 表示，臨床前研究顯示，找到 MCL1 的「開關」是一個非常有價值且極具挑戰的目標，過去從沒有人成功製出針對 MCL1 的小分子抑制劑。
在發現 S63845 小分子後，研究人員首先針對血液腫瘤進行了一系列體外實驗和白老鼠活體實驗：在25類多發性骨髓瘤中，S63845 對其中23類都有抑制效果；針對11類淋巴癌和慢性粒細胞白血病中，S63845 能抑制其中的8個；而對於7類 c-myc 布氏淋巴瘤、8類急性粒細胞白血病，以及來自25位白血病患者的腫瘤細胞，S63845 全都產生了抑制效果。
更加值得一提的是，在適當劑量的藥物作用下，實驗白老鼠的正常細胞完全能抵受 S63845，這意味着病患在將來不再需要忍受副作用帶來的痛苦。
對實體腫瘤而言，研究人員選擇了20類肺癌、9類乳腺癌、12類黑色素瘤進行試驗，發現 S63845 的有效率大約是25%。雖然它在實體腫瘤中並沒有在血液腫瘤中一樣的效果，但研究人員表示，與相應腫瘤的特效藥結合使用的話，治療效果會有顯著提高。
這項研究成果意味着 S63845 的發現，讓能攻克不同種類癌症的「廣譜抗癌藥」成為可能。
This new compound could help kill up to a quarter of all cancer types
DAVID NIELD 27 OCT 2016
Scientists have developed a new compound that's effective at inhibiting the growth of multiple types of cancer models in the lab – slowing as many as a quarter of all known types of cancer.
The molecule, called S63845, works by blocking the protein MCL1, which many different types of cancer cells rely on to grow. And without access to MCL1, the cancer cells die off.
The discovery could help researchers fight blood cancers such as acute myeloid leukemia, lymphoma, and multiple myeloma. Solid tumours – including melanoma and cancers of the lung and breast – could also see new treatments.
"MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body," says one of the team, Guillaume Lessene from the Walter and Eliza Hall Institute in Australia.
"Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival."
Cancerous cells are difficult for the body's immune system to kill, because they can quickly evolve and spread faster than our defences can keep up, and can also evade what's called apoptosis – a form of programmed cell death.
Blasting them with chemotherapy drugs or radiation can be an effective way to combat cancer cells, but these techniques usually take healthy cells along with them, and cause debilitating side effects.
What makes S63845 so promising is that, in addition to cutting off cancer's life support system, it can be given at doses that don't harm normal cells, the team suggests.
The compound is the latest development in a new class of anti-cancer drugs called BH3 mimetics, which target a family of proteins that cancers rely on to sidestep and resist programmed cell death.
"BH3 mimetics inhibit a group of proteins known as the 'pro-survival BCL-2 proteins'," says Lessene. "MCL1 is a member of this protein family, and inhibiting it activates the process of programmed cell death."
It's worth pointing out that research is still at a pre-clinical stage, and the researchers need to run further tests on the compound before turning it into a drug that can be taken safely by human patients. But the early signs are very encouraging.
In fact, the same molecule could be used to stop even more types of cancer in the future.
"This discovery finds new hope for patients," says one of the team, haematologist Andrew Wei, from the Alfred Hospital in Australia. "We consider [S63845] to be a precision drug which can really strike cancer at its core and reduce the defences against cancer survival."
"It's possible that with future research and discoveries that this compound will be amenable and effective against other forms of cancer."
The findings have been published in Nature.
