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▎A new study by WuXi AppTec content team editor "Nature-Cancer" once again demonstrates the huge potential of the existing drug treasure trove.
A drug that is ineffective or outdated for one disease may be able to play a role in the battlefield of other diseases
.
BACE1 inhibitors used to be potential drugs for the treatment of Alzheimer's disease, and the scientific community has also expressed great expectations for it
.
The reason is that the BACE1 protein plays an important role in the production of β-amyloid plaques in the brain, and the latter is one of the main signs of Alzheimer's disease
.
Therefore, researchers have speculated that inhibiting the function of BACE1 can reduce amyloid plaques, which can be used to treat Alzheimer's disease
.
However, the results of clinical trials are disappointing.
The efficacy of BACE1 inhibitors in the treatment of mild to moderate Alzheimer's disease is not obvious, and related fields have stopped continuing to use BACE1 inhibitors
.
But in fact, BACE1 is also expressed on the surface of a type of immune cells that appear in the tumor microenvironment-tumor-associated macrophages (TAM)
.
There are two types of TAM.
Among them, pTAM is the type that promotes tumor growth and causes drug resistance, and there is another type of sTAM that can inhibit tumor growth
.
"If a method can be developed to manipulate the ratio of the two, then many cancers including glioblastoma can be better treated," said Professor Bao Shideng, who led the research
.
Through the drug screening process, they found a BACE1 inhibitor MK-8931 that can effectively cope with pTAM
.
Researchers tried to test on a human glioma cell model, and found that when MK-8931 is present, pTAM can be reprogrammed into sTAM and can promote the phagocytosis of glioma cells by macrophages
.
▲MK-8931 can treat mouse gliomas (picture source: reference [2]) From the observation results, the more sTAM, the more effectively it can remove tumor cells
.
In addition, this drug can achieve better results when combined with low-dose radiation, because radiation can make TAM more likely to penetrate into tumors
.
However, it is not clear why BACE1 inhibitors can promote the transformation of TAM types
.
Research has found three molecules that may be related: interleukin-6 (IL-6), IL-6 receptor (sIL-6), and STAT3 related to the STAT signaling pathway
.
These molecules are expressed in large quantities on pTAM, but are rarely seen on sTAM
.
They will form a special signal transmission pathway with BACE1 to maintain the state of pTAM
.
Therefore, when we interfere with the function of BACE1, the signal of the entire channel will be blocked, and therefore shift towards sTAM
.
Although BACE1 inhibitors have no effect on Alzheimer's disease, its safety has been proven, which means it will be very convenient if it needs to be reused to fight cancer cells
.
"For example, verubecestat has been approved for use in humans," said Professor Bao Shideng.
"This will accelerate the transition of our basic research to clinical applications
.
This is a huge advantage of drug reuse
.
"Reference: [1] Drug designed for Alzheimer's disease may hold promise for treating glioblastoma.
Retrieved Nov 25th, 2021 from https://medicalxpress.
com/news/2021-11-drug-alzheimer-disease-glioblastoma.
html[2 ] Kui Zhai et al, Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells, Nature Cancer (2021).
DOI: 10.
1038/s43018-021-00267-9
A drug that is ineffective or outdated for one disease may be able to play a role in the battlefield of other diseases
.
BACE1 inhibitors used to be potential drugs for the treatment of Alzheimer's disease, and the scientific community has also expressed great expectations for it
.
The reason is that the BACE1 protein plays an important role in the production of β-amyloid plaques in the brain, and the latter is one of the main signs of Alzheimer's disease
.
Therefore, researchers have speculated that inhibiting the function of BACE1 can reduce amyloid plaques, which can be used to treat Alzheimer's disease
.
However, the results of clinical trials are disappointing.
The efficacy of BACE1 inhibitors in the treatment of mild to moderate Alzheimer's disease is not obvious, and related fields have stopped continuing to use BACE1 inhibitors
.
But in fact, BACE1 is also expressed on the surface of a type of immune cells that appear in the tumor microenvironment-tumor-associated macrophages (TAM)
.
There are two types of TAM.
Among them, pTAM is the type that promotes tumor growth and causes drug resistance, and there is another type of sTAM that can inhibit tumor growth
.
"If a method can be developed to manipulate the ratio of the two, then many cancers including glioblastoma can be better treated," said Professor Bao Shideng, who led the research
.
Through the drug screening process, they found a BACE1 inhibitor MK-8931 that can effectively cope with pTAM
.
Researchers tried to test on a human glioma cell model, and found that when MK-8931 is present, pTAM can be reprogrammed into sTAM and can promote the phagocytosis of glioma cells by macrophages
.
▲MK-8931 can treat mouse gliomas (picture source: reference [2]) From the observation results, the more sTAM, the more effectively it can remove tumor cells
.
In addition, this drug can achieve better results when combined with low-dose radiation, because radiation can make TAM more likely to penetrate into tumors
.
However, it is not clear why BACE1 inhibitors can promote the transformation of TAM types
.
Research has found three molecules that may be related: interleukin-6 (IL-6), IL-6 receptor (sIL-6), and STAT3 related to the STAT signaling pathway
.
These molecules are expressed in large quantities on pTAM, but are rarely seen on sTAM
.
They will form a special signal transmission pathway with BACE1 to maintain the state of pTAM
.
Therefore, when we interfere with the function of BACE1, the signal of the entire channel will be blocked, and therefore shift towards sTAM
.
Although BACE1 inhibitors have no effect on Alzheimer's disease, its safety has been proven, which means it will be very convenient if it needs to be reused to fight cancer cells
.
"For example, verubecestat has been approved for use in humans," said Professor Bao Shideng.
"This will accelerate the transition of our basic research to clinical applications
.
This is a huge advantage of drug reuse
.
"Reference: [1] Drug designed for Alzheimer's disease may hold promise for treating glioblastoma.
Retrieved Nov 25th, 2021 from https://medicalxpress.
com/news/2021-11-drug-alzheimer-disease-glioblastoma.
html[2 ] Kui Zhai et al, Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells, Nature Cancer (2021).
DOI: 10.
1038/s43018-021-00267-9
