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Written | Edited by xiao xia | Typesetting by Wang Duoyu | For hundreds of years, Cordyceps, a specialty of the Himalayas, has been used in traditional Chinese medicine to treat cancer and other inflammatory diseases.
Its active ingredient is 3'-deoxyadenosine ( 3'-dA), also known as cordycepin, is a natural nucleoside analogue
.
Nucleoside analogs are the backbone of many oncology treatment options and need to be activated by intracellular enzymes
.
However, because 3'-dA is easily hydrolyzed in the blood by the circulating enzyme adenosine deaminase (ADA), poor cellular uptake, and adenosine kinase (ADK)-dependent activation, only a very small amount of the drug is delivered to the tumor
.
Recently, the research team of the University of Oxford and the biopharmaceutical company NuCana published a titled: The novel nucleoside analogue ProTide NUC-7738 overcomes cancer resistance mechanisms in vitro and in a first-in-human in the famous cancer research academic journal Clinical Cancer Research.
Research papers for Phase 1 clinical trial
.
In order to improve the efficacy of 3'-dA and evaluate its application as an anti-cancer drug in the clinic, NuCana has developed a new type of anti-cancer drug-NUC-7738 using its patented technology ProTide
.
NUC-7738 is derived from cordycepin extracted from Cordyceps sinensis in the Himalayas.
After chemical modification, it can overcome key drug resistance mechanisms and produce high levels of active anti-cancer metabolites in cancer cells.
Its effectiveness is 40 times that of cordycepin.
, Limited side effects
.
A phase 1 clinical trial is currently underway.
The patient tolerates NUC-7738 well and shows encouraging signs of anti-cancer activity.
The research team will carry out further phase 2 clinical trials
.
Life history of Cordyceps First, the research team used ProTide to synthesize pre-activated or monophosphorylated 3'-dA--NUC-7738
.
ProTide combines a protective phosphoramide cap with a nucleoside to deliver a high concentration of active drug to the cell
.
It has been used to produce anticancer nucleoside analogs such as NUC-3373 and NUC-1031
.
In this study, they compared NUC-7738 with the parent compound 3'-dA
.
By measuring the average IC50 of a large number of cancer cell lines, they observed that NUC-7738 showed stronger potency
.
In addition, 3'-dA is dependent on ADA and ADK, but the efficacy of NUC-7738 is mostly not affected by ADA or ADK inhibition
.
In order to identify genes that are resistant to 3'-dA and NUC-7738 after inactivation, the research team used the nearly haploid human cell line HAP1 to screen for insertional mutations
.
The results showed that the inserts in ADK were strongly enriched in 3'-dA-treated cells
.
In the HAP1 cell line and single-cell-derived clone HINT1 knockout cells, the knockout of HINT1 by CRISPR/Cas9 significantly reduced the sensitivity to NUC-7738, but did not reduce the sensitivity to 3'-dA
.
In order to explore the effect of HINT1 on the sensitivity of NUC-7738, the research team classified cancer cell lines into low, medium, and high according to their relative HINT1 mRNA expression levels, and treated them with NUC-7738 or 3'-dA
.
They observed no correlation between HINT1 expression and sensitivity to NUC-7738 or 3'-dA
.
Then, they knocked out HINT1 in the cell line until only minimal residual levels were detected, and again observed no difference in sensitivity to NUC-7738
.
These findings indicate that even low levels of HINT1 are sufficient to activate NUC-7738
.
Next, the research team used beagle dogs to determine the maximum non-toxic dose of NUC-7738
.
The success of cell and animal experiments led them to launch the NuTide: 701 trial, which is the first phase I dose amplification/expansion study in humans to evaluate the safety of NUC-7738 in patients with advanced solid tumors resistant to conventional treatments/ Tolerability, pharmacokinetics and pharmacodynamics
.
This human clinical trial is currently being conducted in 3 centers in the UK: Edinburgh, Newcastle and Oxford
.
As of June 1, 2021, 28 patients with advanced cancer have been registered
.
So far, NUC-7738 is well tolerated and no dose limiting toxicity has been reported
.
They also obtained a specimen from a melanoma patient undergoing treatment and compared it with the specimen before the start of treatment
.
The results showed that NUC-7738 treatment down-regulated HINT1 and NF-κB
.
RNA sequencing identified 1,069 genes that were differentially expressed twice
.
Among them, the TNF-α signal was significantly down-regulated through the NF-κB pathway, and the expression of some cancer-promoting target genes and melanoma-related genes was reduced by 7-40 times
.
These results show encouraging signs of anti-cancer activity and indicate that NF-κB signaling may be a common feature after NUC-7738 treatment
.
In summary, the study shows that by overcoming key cancer drug resistance mechanisms, NUC-7738 has a higher cytotoxic activity than cordycepin against a series of cancer cells
.
In addition, clinical trials showed good tolerability and encouraging signs of anti-cancer activity, supporting the further clinical evaluation of NUC-7738 as a new cancer treatment
.
Paper link: https://clincancerres.
aacrjournals.
org/content/early/2021/09/08/1078-0432.
CCR-21-1652 Special reminder: This article only truthfully introduces the latest scientific research progress and does not constitute purchase or use advice
.
Open to reprint, welcome to forward to the circle of friends and WeChat group
Its active ingredient is 3'-deoxyadenosine ( 3'-dA), also known as cordycepin, is a natural nucleoside analogue
.
Nucleoside analogs are the backbone of many oncology treatment options and need to be activated by intracellular enzymes
.
However, because 3'-dA is easily hydrolyzed in the blood by the circulating enzyme adenosine deaminase (ADA), poor cellular uptake, and adenosine kinase (ADK)-dependent activation, only a very small amount of the drug is delivered to the tumor
.
Recently, the research team of the University of Oxford and the biopharmaceutical company NuCana published a titled: The novel nucleoside analogue ProTide NUC-7738 overcomes cancer resistance mechanisms in vitro and in a first-in-human in the famous cancer research academic journal Clinical Cancer Research.
Research papers for Phase 1 clinical trial
.
In order to improve the efficacy of 3'-dA and evaluate its application as an anti-cancer drug in the clinic, NuCana has developed a new type of anti-cancer drug-NUC-7738 using its patented technology ProTide
.
NUC-7738 is derived from cordycepin extracted from Cordyceps sinensis in the Himalayas.
After chemical modification, it can overcome key drug resistance mechanisms and produce high levels of active anti-cancer metabolites in cancer cells.
Its effectiveness is 40 times that of cordycepin.
, Limited side effects
.
A phase 1 clinical trial is currently underway.
The patient tolerates NUC-7738 well and shows encouraging signs of anti-cancer activity.
The research team will carry out further phase 2 clinical trials
.
Life history of Cordyceps First, the research team used ProTide to synthesize pre-activated or monophosphorylated 3'-dA--NUC-7738
.
ProTide combines a protective phosphoramide cap with a nucleoside to deliver a high concentration of active drug to the cell
.
It has been used to produce anticancer nucleoside analogs such as NUC-3373 and NUC-1031
.
In this study, they compared NUC-7738 with the parent compound 3'-dA
.
By measuring the average IC50 of a large number of cancer cell lines, they observed that NUC-7738 showed stronger potency
.
In addition, 3'-dA is dependent on ADA and ADK, but the efficacy of NUC-7738 is mostly not affected by ADA or ADK inhibition
.
In order to identify genes that are resistant to 3'-dA and NUC-7738 after inactivation, the research team used the nearly haploid human cell line HAP1 to screen for insertional mutations
.
The results showed that the inserts in ADK were strongly enriched in 3'-dA-treated cells
.
In the HAP1 cell line and single-cell-derived clone HINT1 knockout cells, the knockout of HINT1 by CRISPR/Cas9 significantly reduced the sensitivity to NUC-7738, but did not reduce the sensitivity to 3'-dA
.
In order to explore the effect of HINT1 on the sensitivity of NUC-7738, the research team classified cancer cell lines into low, medium, and high according to their relative HINT1 mRNA expression levels, and treated them with NUC-7738 or 3'-dA
.
They observed no correlation between HINT1 expression and sensitivity to NUC-7738 or 3'-dA
.
Then, they knocked out HINT1 in the cell line until only minimal residual levels were detected, and again observed no difference in sensitivity to NUC-7738
.
These findings indicate that even low levels of HINT1 are sufficient to activate NUC-7738
.
Next, the research team used beagle dogs to determine the maximum non-toxic dose of NUC-7738
.
The success of cell and animal experiments led them to launch the NuTide: 701 trial, which is the first phase I dose amplification/expansion study in humans to evaluate the safety of NUC-7738 in patients with advanced solid tumors resistant to conventional treatments/ Tolerability, pharmacokinetics and pharmacodynamics
.
This human clinical trial is currently being conducted in 3 centers in the UK: Edinburgh, Newcastle and Oxford
.
As of June 1, 2021, 28 patients with advanced cancer have been registered
.
So far, NUC-7738 is well tolerated and no dose limiting toxicity has been reported
.
They also obtained a specimen from a melanoma patient undergoing treatment and compared it with the specimen before the start of treatment
.
The results showed that NUC-7738 treatment down-regulated HINT1 and NF-κB
.
RNA sequencing identified 1,069 genes that were differentially expressed twice
.
Among them, the TNF-α signal was significantly down-regulated through the NF-κB pathway, and the expression of some cancer-promoting target genes and melanoma-related genes was reduced by 7-40 times
.
These results show encouraging signs of anti-cancer activity and indicate that NF-κB signaling may be a common feature after NUC-7738 treatment
.
In summary, the study shows that by overcoming key cancer drug resistance mechanisms, NUC-7738 has a higher cytotoxic activity than cordycepin against a series of cancer cells
.
In addition, clinical trials showed good tolerability and encouraging signs of anti-cancer activity, supporting the further clinical evaluation of NUC-7738 as a new cancer treatment
.
Paper link: https://clincancerres.
aacrjournals.
org/content/early/2021/09/08/1078-0432.
CCR-21-1652 Special reminder: This article only truthfully introduces the latest scientific research progress and does not constitute purchase or use advice
.
Open to reprint, welcome to forward to the circle of friends and WeChat group