By using a compound derived from a Himalayan fungus and used for centuries in Chinese medicine as a jumping off point, scientists have developed a new chemotherapy drug with powerful anti-cancer effects. Doing so involved chemically altering the compound to better infiltrate cancerous cells, which proved to boost its potency by up to 40 times.
Editor's note: Readers often ask us for follow-ups on memorable stories. What has happened to this story over the years? This article was originally published in 2021 but has been re-edited and updated with new information current as of April 25, 2025. Enjoy!
The 2021 research was carried out by University of Oxford scientists in collaboration with biopharmaceutical company Nucana, and began with a compound called Cordycepin. This naturally-occurring nucleoside analogue has been used to treat inflammatory disease and cancer for hundreds of years, but runs into several barriers that severely limit its effectiveness when deployed to tackle tumors.
This is largely because as Cordycepin enters the bloodstream, it is rapidly broken down by an enzyme called ADA. What is left then needs to be carried into cancer cells by a nucleoside transporter, and then converted into an anti-cancer metabolite called 3’-dATP. This is a lot of hoops for the humble, naturally-occurring Cordycepin to jump through and means only meager amounts wind up making it into the tumor.
NuCana looked to harness the anti-cancer potential of Cordycepin and better equip it to navigate these considerable roadblocks, through what it calls ProTide technology. This is designed specifically to address the shortcomings of nucleoside analogues. It works by attaching small chemical groups to the compound that make it more resistant to breakdown in the bloodstream, and also enables them to enter cancer cells without the help of nucleoside transporters. The upshot is that far greater levels of anti-cancer metabolites are generated and activated inside tumor cells.
This enhanced form of Cordycepin was dubbed NUC-7738. This novel chemotherapy drug was initially assessed through in vitro studies, where it overcame the resistance mechanisms that inhibit its parent compound. Tumor samples obtained from Phase I clinical trials were then used to probe its effectiveness in humans, with these experiments validating the earlier findings.
When the research was published in the journal Clinical Cancer Research back in 2021, the authors concluded that NUC-7738 had as much as 40 times the potency of the naturally occurring Cordycepin, with limited toxic side effects. The Phase 1 trial has since moved into the Phase 2 stage, involving a small number of patients with advanced solid tumors who had "exhausted all treatment options."
The compound was combined with a checkpoint inhibitor called pembrolizumab for this part of the NuTide:701 study, and NuCana presented final data at the ESMO Congress in Barcelona last year. The patient cohort was made up of 12 patients ranging from 42 to 74 years of age, who had all "received at least two prior lines of PD-1 inhibitor therapy." The company reported that the drug combination had managed to get the disease under control for nine of those (75%), with a 55% reduction in tumor volume being noted in one patient. Seven of the 12 "had a progression free survival time of greater than five months, which is highly atypical in this patient population." And the company reported a "favorable safety profile" for the cohort.
"The translational data that has been generated in this study and in previous non-clinical studies give us confidence that the effects we are seeing are a result of NUC-7738 making previously resistant tumors sensitive to rechallenge with PD-1 inhibitors by targeting multiple aspects of the tumor microenvironment," said NuCana founder and CEO, Hugh S. Griffith in a press statement. A patent application was made in September last year "covering NUC-7738’s composition of matter."
Encouraged by trial results over the last few years, the company announced last month that Phase 2 trials involving a larger cohort would commence some time in 2025, and that talks with the US Food and Drug Administration are in the pipe to discuss the roadmap to approval.
Sources: University of Oxford, NoCana [1,2,3]
A version of this article was originally published in 2021
