無論哪種癌症的致命腦轉移，都有救了！ 肺癌康復圈 腫瘤並不可怕，可怕的是轉移，這句話大家一定耳熟能詳。而腦轉移更是預後顯著惡化的先兆！據統計，原發性腫瘤有10％至40％的概率會發生腦轉移，目前針對腫瘤腦轉移的方案主要是手術和放療，但收效甚微。 雖然近年來在靶向治療或免疫治療方面也曾出現過一些替代方案，但即便是在最佳狀況下，也僅有20％的患者能夠因此獲益。近日，研究小組在Nature Medicine雜誌上發表的一項研究表明，對腦轉移的病人使用silibinin可以減少病變，且不會造成任何不良影響，這種化合物有望成為治療腦轉移的有效且安全的替代方案。
Silibinin是何方神聖？早在2015年的美國癌症研究協會（AACR）年會上，就出現過它的大名——silibinin，中文名水飛薊賓，是一種存在於牛奶薊種子內的非毒性，潛在的化學預防劑。
Silibinin停止大腸腫瘤幹細胞生長 當時來自科羅拉多大學的學者展示了最新的研究結果關於silibinin能減慢結直腸癌幹細胞生長的能力。silibinin治療後採樣的腫瘤幹細胞重新注入到新模型上，細胞未能發展成具有同樣侵襲性的腫瘤，即使在沒有再服用水飛薊賓的情況下。在silibinin餵養的小鼠腫瘤內，腫瘤幹細胞數目很少，腫瘤體積較小，代謝水準較低，並表現出新的血管生長水準下降。 更重要的是，silibinin餵養的小鼠的腫瘤幹細胞失去了分裂繁殖的能力。研究人員表示具體的分子機制的發現還需要一定的研究，確認silibinin在癌症的預防和或治療的人體臨床實驗也在計畫之中。研究者嘗試在小鼠中把這種STAT3基因從反應性星形膠質細胞中消除，並結合silibinin，發現其腦轉移得到了顯著改善。而後，研究者進行了18名肺癌腦轉移患者的佇列研究，結果顯示：75％的患者在腦轉移水準呈陽性反應。 其中3名患者（20％）顯示總反應，10名（55％）顯示部分反應。平均存活率為15.5個月，而對照組僅為4個月。 對於任何類型的腦轉移，這種治療方法都可以發揮效力，而無論其原發腫瘤是什麼。但是儘管取得了積極的成果，但還是必須對這種化合物進行進一步的試驗。並且值得關注的是，這是史上第一個針對腦轉移的靶向治療方法，可以說是腦轉移治療的里程碑，由它帶來的積極意義也勢必將不可估量。
Silibinin (INN), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silicristin, silidianin, and others.
A new therapy proves effective against brain metastasis June 11, 2018, The National Centre for Cancer Research. A study published in Nature Medicine by a team led by Manuel Valiente, head of the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO), shows that the administration of silibinin in patients with brain metastasis reduces lesions without causing any adverse effects. This preliminary trial provides proof of concept that this compound could be a new effective and safe alternative to treat brain metastasis. "We have demonstrated, taking into account all the considerations relevant to a compassionate use trial such as ours, that we can successfully treat brain metastasis," says Valiente. "This treatment could also be valid for any type of brain metastasis, regardless of the primary tumour that generated it," he added. It is estimated that between 10 percent and 40 percent of primary tumours generate metastasis in the brain, a situation that worsens patient prognosis considerably. Few advances have been made in terms of treatment; currently, brain metastasis is still being treated with surgery and/or radiotherapy. In recent years, some alternatives have appeared in terms of targeted therapies or immunotherapy, but the percentage of patients who might benefit from these therapies is just 20 percent in the best-case scenario.
The tumour microenvironment as a critical factor in metastasis The role of the cellular context (microenvironment) in which a tumour develops is becoming increasingly important, not only with a view to understanding how cancer cells grow, but also to know how to attack them. In the brain, an inhospitable environment for any foreign element, the role of the microenvironment is relevant and understudied. Valiente and his group have been studying this brain microenvironment for years, focusing in particular on two elements: One, a population of cells known as astrocytes, which respond to damage by entering into a reactive state and which are associated with metastasis. Two, the STAT3 gene, which research has established is involved with brain metastasis. As shown in this research, the activation of STAT3 is significant in a subpopulation of reactive astrocytes that are key to establishing a pro-metastatic environment. When this gene is eliminated from the reactive astrocytes, the viability of brain metastasis is compromised. With this information on the table, Valiente's research group used a novel drug screening strategy developed by them called METPlatform. This tool is capable of analysing the relationship between hundreds of compounds and the metastatic cells found in the target organ simultaneously; in this case, in the brain. "This strategy allows us to assess experimental drugs as well as those that are already in use for other types of pathologies that might or might not be linked to cancer. We believe that by using METPlatform we can be more efficient in developing new therapeutic options, since we can study the metastatic cell growing in the organ being colonised," explained Valiente. One of the compounds tested in this preparation was silibinin, whose anti-tumour potential had previously been established by Joaquim Bosch, Head of the Lung Cancer Unit at Catalonia's Cancer Institute (ICO) in Girona, and co-author of this study. "In 2016, we reported positive brain responses in two patients with no other treatment options who received silibinin, but we did not know how it worked. Thanks to this research, led by Valiente's group, we now understand how it acts at the level of the brain," said Bosch. A new therapeutic concept with encouraging results Following the good results obtained by blocking STAT3 with silibinin in mice, the authors established a cohort of 18 patients with lung cancer and brain metastasis for whom compassionate use of this drug was granted in combination with standard treatment. 75 percent of the patients reacted positively at the level of brain metastasis. Three patients (20 percent) displayed a total response, and 10 (55 percent) a partial response. Average survival rate was 15.5 months, whereas in the control group (composed of patients treated for this disease in the same institution during 2015-2016) it was four months. "Our treatment mainly targets the brain environment that has been altered by metastasis. This is a new therapeutic concept," said Valiente. "We are also attacking an alteration that is only seen when there is brain metastasis, and which is necessary for its viability," he added. "We have explored whether therapies targeting organ-specific survival mechanisms could be a novel approach to treat brain metastasis," explains Neibla Priego, first author of the study. In spite of the positive results, further trials must be conducted with this compound before it can be incorporated into clinical practice. Researchers have been trying to launch such trials for months, but so far, they have not been able to secure the funding they need in order to do so. "This present research describes the first targeted therapy for brain metastasis that acts by attacking its tumour microenvironment. However, more data are needed before it can be incorporated into clinical practice. The 18 patients treated so far indicate that it would be feasible to administer this treatment and that it could be very relevant at a clinical level. Clinical trials, with silibinin or with drugs that act against this target, are crucial if we wish to make this new therapeutic option available to patients," concluded Bosch, head of the clinical study, and Valiente, research director. Patients with brain metastasis have traditionally been excluded from clinical trials because of their poor prognosis. "It now appears that there is a move toward not excluding them given their growing importance in clinical practice. In this regard, we hope that with METPlatform we will be able to help build confidence so that new drugs can be evaluated on these patients," adds Valiente.
STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
Nature Medicine (2018) |The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.
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