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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, which is a A natural nucleoside analogue
.
Nucleoside analogs are the backbone of many oncology treatment options and need to be activated by intracellular enzymes
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.
Cordyceps life history
Cordyceps life history Cordyceps life historyFirst, 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
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 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
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
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
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
.
Original source:
Original source:Hagen Schwenzer, Erica De Zan, Mustafa Elshani, et al.
The novel nucleoside analogue ProTide NUC-7738 overcomes cancer resistance mechanisms in vitro and in a first-in-human Phase 1 clinical trial.
Clinical Cancer Research, 2021.
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