黑素瘤的葡萄糖成瘾为新的治疗--切断癌细胞的葡萄糖供应,提供了希望

Melanoma’s glucose addiction offers hope for new treatment

 

墨尔本的研究人员发现,黑色素瘤细胞的生长和转移依赖葡萄糖,这为通过阻断其燃料来源来阻止肿瘤生长的疗法铺平了道路。

 

黑素瘤是澳大利亚最致命的癌症,每年夺走1500条生命。如果没有治疗,预期寿命大约为8个月。

 

大约40%的黑色素瘤是由BRAF基因的突变驱动的,并依赖于葡萄糖来驱动其积极的生长。

这项研究由博士后科学家蒂芙尼·帕门特(Tiffany Parmenter)领导,并由教授罗德·希克斯(Rod Hicks)和格兰特·姆卡图尔(Grant McAurthur)共同撰写。研究成果发表在《癌症发现》杂志上。

研究人员在临床实践中发现了许多模式,并开始了解支持这些变化的科学机制。

 

他们注意到由BRAF基因驱动的肿瘤特别高的葡萄糖的使用,这在药物治疗后很快就被关闭了——这表明药物正在起作用。

 

“虽然我们知道这些药物对有这种特殊突变的患者来说是非常有效的,但它只会让他们停止生长一段时间——有时是几年,但不幸的是,有时它只会在几周内控制它。”合著者罗德尼·希克斯教授说。

 

研究人员还注意到,在肿瘤开始再次生长之前,黑色素瘤的葡萄糖供应被重新打开,并对药物产生了抗药性。

 

该研究小组在三年内使用了一系列不同的实验——包括基因分析、细胞培养分析和用药物孵育细胞——将发生的事情拼凑起来。

 

希克斯教授说:“我们发现,细胞在需要生长时对葡萄糖上瘾他说,有些细胞如此上瘾,一旦供应受到威胁,它们就会自杀,而另一些则能活下来。

 

下一步是开发利用“切断燃料供应”或阻断控制葡萄糖摄取和使用的基因,从而杀死剩余癌细胞的疗法。

 

但希克斯教授说,不幸的是,阻断黑色素瘤的葡萄糖供应并不像少吃糖那么简单。

“你的大脑、心脏和其他所有的组织都需要糖,所以这不是一个可行的建议。”我们要做的是针对癌细胞中葡萄糖的特定用途。

 

Epworth皮肤病研究中心主任Rodney Sinclair教授说,这些癌症是出了名的难以治疗。

他说:“黑素瘤有把“种子”撒入血液和淋巴管的趋势,这种“种子”可以潜伏数年,然后再激活。

 

“种子很难被发现,很难根除。”一旦重新激活,它们就能适应并抵抗对其他类型癌症有效的化疗。

 

虽然现代药物能够缩小肿瘤,但他说,它们通常不会完全消失。

随着时间的推移,剩下的残余肿瘤会找到抵抗化疗的方法,然后反弹回来。因此,这些疗法并不是治愈,而是将生命延长到一到两年,然后病人最终死于黑素瘤。

 

癌症生物学家达伦·桑德斯(Darren Saunders)Garvan研究所的实验室负责人,他说这项研究是新联合疗法发展的重要一步。

 

他说:“这项研究发现了一种潜在的新途径,并证明了使用BRAF抑制剂与针对糖酵解的药物结合的概念。

 

糖酵解是细胞代谢的一个特殊的分支,它将糖(葡萄糖)转化为能量,并为新细胞的构件。

“对于癌症细胞如何重新规划新陈代谢,将糖、脂肪和氨基酸等燃料与正常细胞区别开来,这是一种新兴的认识。”

 

“这种重新编程是一个非常吸引人的新疗法和研究热点。”

 

 

参考文献:

Melanoma’s glucose addiction offers hope for new treatment

 

Melanoma cells are dependent on glucose to grow and spread, Melbourne researchers have found, paving the way for therapies that can halt cancer growth by blocking its fuel source.

 

Melanoma is the most deadly cancer in Australia, claiming 1,500 lives each year. Without treatment the life expectancy is around eight months from diagnosis.

 

Around 40% of melanomas are driven by mutations in the BRAF gene and rely on glucose to drive their aggressive growth.

 

The study – led by post-doctoral scientist Tiffany Parmenter and co-authored by professors Rod Hicks and Grant McAurthur at the Peter Peter McCallum Cancer Centre – was published today in the journal Cancer Discovery.

 

The researchers saw a number of patterns in clinical practice and set out to understand the scientific mechanisms that underpinned these changes in patients.

 

They noticed that tumours driven by BRAF genes had particularly high use of glucose, which was turned off very rapidly after drug therapy – this indicated the medication was working.

 

While we know these drugs are incredibly effective in patients who have this particular mutation, it will only stop them growing for a period of time – sometimes years, but unfortunately sometimes it only keeps it under control for weeks,” said co-author Professor Rodney Hicks.

 

The researchers also noticed that before the tumours started to grow again, the melanoma’s glucose supply was turned back on and became resistant to the effects of the drug.

 

The team used a series of different experiments over three years – including genetic analysis, cell culture analysis and tests incubating cells with drugs – to piece together what was occurring.

 

We found that the cells were ‘addicted’ to glucose in their need to grow,” Prof Hicks said. Some were so addicted, they would kill themselves as soon as the supply was threatened, while others were able to survive, he said.

 

The next step is to develop therapies that kill the remaining cancer cells by “cutting off the fuel supply” or blocking the raft of genes that regulate the uptake and use of glucose.

 

But unfortunately, blocking the the melanoma’s glucose supply was not as simple as eating less sugar, Prof Hicks said.

 

Your brain and heart and all your other tissues need sugar so that’s not a viable proposition. What we want to do is target a very specific use of glucose in cancer cells.”

 

Professor Rodney Sinclair, Head of the Epworth Dermatology Research Centre, said these cancers were notoriously difficult to treat.

 

Melanoma has a tendency to drop seeds into the blood stream and lymphatics that can lay dormant for years before reactivating,” he said.

 

The seeds are hard to detect and hard to eradicate. Once reactivated they are adaptable and resist chemotherapy that is effective for other types of cancer.”

 

Although modern drugs were able to shrink tumours, he said, they usually did not disappear completely.

 

The remaining residual tumour over time finds a way to resist the chemotherapy and then rebounds back. So, rather than a cure, these treatments prolong life by anywhere up to a year or two and then the patient ultimately succumbs to the melanoma.”

 

Cancer biologist Darren Saunders, laboratory head at the Garvan Institute, said the study was important step forward in the development of new combination therapies.

 

This study has identified a potential new avenue, and proof of concept, for using BRAF inhibitors in combination with drugs targeting glycolysis,” he said.

 

Glycolysis is a particular arm of cellular metabolism that converts sugar (glucose) into energy and building blocks for new cells.

 

"There is a rapidly emerging understanding of how cancer cells reprogram their metabolism to use fuels like sugar, fats and amino acids differently to normal cells.

 

"This reprogramming is a highly attractive target for new therapies and the subject of intense research interest.”

 

https://theconversation.com/melanomas-glucose-addiction-offers-hope-for-new-treatment-25266