O. sinensis growing out of a caterpillar. (IgorChus/Getty Images)

Cancer Drug Derived From Himalayan 'Caterpillar Fungus' Smashes Early Clinical Trial

12 OCTOBER 2021

A new kind of chemotherapy derived from a molecule found in a Himalayan fungus has been revealed as a potent anti-cancer agent, and may in the future provide a new treatment option for patients with cancer.

 

NUC-7738, synthesized by researchers at the University of Oxford in partnership with UK-based biopharmaceutical company NuCana, is still in the experimental testing stages and isn't available as an anti-cancer medication yet – but newly reported clinical trial results bode well for the drug candidate.

The active ingredient in NUC-7738 is called cordycepin, which was first found in the parasitic fungus species Ophiocordyceps sinensis (also known as caterpillar fungus because it kills and mummifies moth larva), used as a herbal remedy in traditional Chinese medicine for centuries.

Cordycepin, also known as 3'-deoxyadenosine (or 3'-dA), is a naturally occurring nucleoside analogue, reported to offer a range of anti-cancer, anti-oxidant, and anti-inflammatory effects, which goes some way to explaining why the fungus is sometimes called the world's most valuable parasite.

Naturally occurring cordycepin extracted from O. sinensis does have its drawbacks, however, including that it is broken down quickly in the bloodstream – with a half-life of 1.6 minutes in plasma – by the enzyme adenosine deaminase, or ADA. It also shows poor uptake into cells, meaning the molecule's actual potency against tumor cells in the body is greatly diminished.

 

To amplify cordycepin's potential as an anti-cancer agent, NUC-7738 makes use of a number of engineered advantages, allowing it to enter cells independently of nucleoside transporters, such as Human Equilibrative Nucleoside Transporter 1 (hENT1).

Unlike naturally occurring cordycepin, NUC-7738 doesn't rely on hENT1 to gain access to cells, and other tweaks to the molecule mean it's pre-activated (bypassing the need for the enzyme adenosine kinase), and is also resistant to breaking down in the bloodstream, with built-in protection against ADA.

According to a new study on NUC-7738, these changes make the drug candidate's anti-cancer properties up to 40 times more potent than cordycepin when tested against a range of human cancer cell lines.

Moreover, early results from the first in-human clinical trial of NUC-7738 appear to be positive so far too. The Phase 1 trial, which began in 2019 and is still ongoing, has so far involved 28 patients with advanced tumors that were resistant to conventional treatment.

So far, weekly escalating doses of NUC-7738 given to this cohort have been tolerated well by the patients, who have shown "encouraging signals of anti-tumor activity and prolonged disease stabilization", the researchers report in their paper.

"These findings provide proof of concept that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and support the further clinical evaluation of NUC-7738 as a novel cancer treatment."

While it's certainly a promising start, it will still be some time before NUC-7738 becomes available to patients outside the trial.

Planning is currently underway for Phase 2 of the trial, once the safety of the drug has been more thoroughly demonstrated, and once the recommended regimen for Phase 2 patients has been identified.

The findings are reported in Clinical Cancer Research.