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▎WuXi AppTec Content Team Editor Recently, scientists at McMaster University in Canada found that a catalytic enzyme involved in regulating the pyrimidine synthesis process is expected to become a key target for the treatment of medulloblastoma - in mouse models, blocking the activity of the enzyme can prevent the growth of MYC amplified medulloblastoma
。 These research results have now been compiled and published in
the well-known academic journal Cancer Cell.
Medulloblastoma is the most common pediatric brain cancer in children, and it is also a properly treatable tumour with a survival rate of about 80%
if medical intervention is done before spreading.
But in addition to surgery, most cases require chemotherapy and radiation, which can impair brain development and set the stage
for later complications.
Now, the treatment of this persistent disease has taken a turn for the better, and scientists have found that the use of inhibitors of DHODH (dihydroorotic acid dehydrogenase) has successfully inhibited the growth and spread of MYC amplified medulloblastoma, the most aggressive type of medulloblastoma
.
DHODH is a key part of the neonatal pyrimidine synthesis pathway, which affects the production of DNA and RNA, and has previously shown that DHODH is involved in
tumor growth 。 Drugs targeting DHODH have become available, such as Sanofi's Arava and Aubagio, both inhibitors of DHODH and have been approved by the US FDA for the treatment of rheumatoid arthritis and multiple sclerosis, other potential indications (including viral infections and several other cancers) are still under investigation, and the findings of this study undoubtedly provide a theoretical basis
for the application of DHODH inhibitors in medulloblastoma.
In this study, the scientists screened the genome and metabolic processes of MYC amplified medulloblastoma and finally set their sights on DHODH - they found that the neopyrimidine synthesis pathway in tumor cells was altered, and knocking out DHODH could stop the growth
of medulloblastoma.
Subsequently, the scientists began to explore whether oral DHODH inhibitors could stop tumor growth
in medulloblastoma mice.
They used a compound called BAY2402234 to treat a mouse model of MYC amplified medulloblastoma, a compound molecule used by Bayer to treat acute myeloid leukemia and glioma
until January.
The researchers found that the compound was able to slow the growth of medulloblastoma and improve survival in mice, increasing their lifespan from 28 days in the control group to about 38 days (average survival time in the BAY2402234 treatment group).
Although the study did not assess whether the compound had an effect on brain development in young mice, the researchers found no harm
to neural stem cells cultured in vitro.
Conversely, radiation affects neural stem cells in children and adults and is thought to be the main cause of radiation-related brain damage; Chemotherapy has also been shown to kill healthy brain cells, which may be responsible
for what patients describe as the "chemo-brain" phenomenon.
As Dr.
William Gwynne, lead author of the paper, said in a press release: "This potential treatment will allow us to kill weeds and save the developing brain flower
.
" DHODH targets are promising, but it is still a few years before we reach clinical trials
.
This potential new therapy, unlike current therapies, is not toxic
to the developing brain.
Image
source: 123RF
WuXi AppTec provides integrated, end-to-end new drug development and manufacturing services to the global biopharmaceutical industry, covering chemical drug development and manufacturing, biological research, preclinical testing and clinical trial development, cell and gene therapy development, testing and manufacturing
.
If you have relevant business needs, please click the picture below to fill in the specific information
.
▲If you have any business needs, please press and hold to scan the QR code above, or
。 These research results have now been compiled and published in
the well-known academic journal Cancer Cell.
Medulloblastoma is the most common pediatric brain cancer in children, and it is also a properly treatable tumour with a survival rate of about 80%
if medical intervention is done before spreading.
But in addition to surgery, most cases require chemotherapy and radiation, which can impair brain development and set the stage
for later complications.
Now, the treatment of this persistent disease has taken a turn for the better, and scientists have found that the use of inhibitors of DHODH (dihydroorotic acid dehydrogenase) has successfully inhibited the growth and spread of MYC amplified medulloblastoma, the most aggressive type of medulloblastoma
.
DHODH is a key part of the neonatal pyrimidine synthesis pathway, which affects the production of DNA and RNA, and has previously shown that DHODH is involved in
tumor growth 。 Drugs targeting DHODH have become available, such as Sanofi's Arava and Aubagio, both inhibitors of DHODH and have been approved by the US FDA for the treatment of rheumatoid arthritis and multiple sclerosis, other potential indications (including viral infections and several other cancers) are still under investigation, and the findings of this study undoubtedly provide a theoretical basis
for the application of DHODH inhibitors in medulloblastoma.
In this study, the scientists screened the genome and metabolic processes of MYC amplified medulloblastoma and finally set their sights on DHODH - they found that the neopyrimidine synthesis pathway in tumor cells was altered, and knocking out DHODH could stop the growth
of medulloblastoma.
Image source: 123RF
Subsequently, the scientists began to explore whether oral DHODH inhibitors could stop tumor growth
in medulloblastoma mice.
They used a compound called BAY2402234 to treat a mouse model of MYC amplified medulloblastoma, a compound molecule used by Bayer to treat acute myeloid leukemia and glioma
until January.
The researchers found that the compound was able to slow the growth of medulloblastoma and improve survival in mice, increasing their lifespan from 28 days in the control group to about 38 days (average survival time in the BAY2402234 treatment group).
Although the study did not assess whether the compound had an effect on brain development in young mice, the researchers found no harm
to neural stem cells cultured in vitro.
Conversely, radiation affects neural stem cells in children and adults and is thought to be the main cause of radiation-related brain damage; Chemotherapy has also been shown to kill healthy brain cells, which may be responsible
for what patients describe as the "chemo-brain" phenomenon.
As Dr.
William Gwynne, lead author of the paper, said in a press release: "This potential treatment will allow us to kill weeds and save the developing brain flower
.
" DHODH targets are promising, but it is still a few years before we reach clinical trials
.
This potential new therapy, unlike current therapies, is not toxic
to the developing brain.
Image
source: 123RF
Given these findings and the fact that BAY2402234 has been proven safe in humans in clinical trials, the researchers call for further optimization of preclinical studies of DHODH inhibitors in medulloblastoma, either alone or in combination with other treatments
.
The researchers wrote in the paper, "If these inhibitor molecules perform well, then they should be translated into clinical studies
.
" ”
WuXi AppTec provides integrated, end-to-end new drug development and manufacturing services to the global biopharmaceutical industry, covering chemical drug development and manufacturing, biological research, preclinical testing and clinical trial development, cell and gene therapy development, testing and manufacturing
.
If you have relevant business needs, please click the picture below to fill in the specific information
.
▲If you have any business needs, please press and hold to scan the QR code above, or
