Oxford University researchers have worked in collaboration with industry leaders NuCana to assess a novel chemotherapy drug derived from a fungus. A study in Clinical Cancer Research has shown that the new drug NUC-7738, developed by NuCana, has a up to 40 times greater potency for killing cancer cells than its parent compound, with limited toxic side effects.
The naturally-occurring nucleoside analogue known as Cordycepin (a.k.a 3’-deoxyadenosine) is found in the Himalayan fungus Cordyceps sinensis and has been used in traditional Chinese medicine for hundreds of years to treat cancers and other inflammatory diseases. However, it breaks down quickly in the blood stream, so a minimal amount of cancer-destroying drug is delivered to the tumour. In order to improve its potency and clinically assess its applications as a cancer drug, biopharmaceutical company NuCana has developed Cordycepin into a clinical therapy, using their novel ProTide technology, to create a chemotherapy drug with dramatically improved efficacy.
Once inside the body, Cordycepin requires transport into cancer cells by a nucleoside transporter (hENT1), it must be converted to the active anti-cancer metabolite, known as 3’-dATP, by a phosphorylating enzyme (ADK), and it is rapidly broken down in the blood by an enzyme called ADA. Together, these resistance mechanisms associated with transport, activation and breakdown result in insufficient delivery of anti-cancer metabolite to the tumour. NuCana have utilised novel ProTide technology to design a therapy that can bypass these resistance mechanisms and generate high levels of the active anti-cancer metabolite, 3’-dATP, inside cancer cells.
ProTide technology is a novel approach for delivering chemotherapy drugs into cancer cells. It works by attaching small chemical groups to nucleoside analogues like Cordycepin, which are then later metabolised once it has reached the patient’s cancer cells, releasing the activated drug. This technology has already been successfully used in the FDA approved antiviral drugs Remsidivir and Sofusbuvir to treat different viral infections such as Hepatitis C, Ebola and COVID-19.
The results of the study published in Clinical Cancer Research suggest that by overcoming key cancer resistance mechanisms, NUC-7738 has greater cytotoxic activity than Cordycepin against a range of cancer cells.
Oxford researchers and their collaborators in Edinburgh and Newcastle are now assessing NUC-7738 in the Phase 1 clinical trial NuTide:701, which tests the drug in patients with advanced solid tumours that were resistant to conventional treatment. Early results from the trial have shown that NUC-7738 is well tolerated by patients and shows encouraging signs of anti-cancer activity.
Further Phase 2 clinical trials of this drug are now being planned in partnership with NuCana, to add to growing number of ProTide technology cancer drugs that are being developed to treat cancer.
About this study
This study was led by Prof Sarah Blagden and Dr Hagen Schwenzer, in partnership with NuCana via the Clinical Positioning Network: an Oxford Cancer service that partners commercial organisations with leading academics to clinical develop novel cancer diagnostics and therapeutics. Additional partners involved in this project include researchers at the Universities of St Andrew’s and Cardiff. NuCana in collaboration with a team in Cardiff University, synthesised the ProTide version of 3’-deoxyadenosine or Cordycepin called NUC-7738. ProTide technology was invented by NuCana's late Chief Scientific Officer, Professor Christopher McGuigan at Cardiff University. In vitro research was conducted at the Universities of Oxford and St Andrew’s. The clinical trial was led from the Oxford Early Phase Clinical Trials Unit, with additional recruitment in Edinburgh and Newcastle.
NuCana® is a clinical-stage biopharmaceutical company focused on significantly improving treatment outcomes for cancer patients by applying ProTideTM technology to transform some of the most widely prescribed chemotherapy agents, nucleoside analogues, into more effective and safer medicines. While these conventional agents remain part of the standard of care for the treatment of many solid and haematological tumours, their efficacy is limited by cancer cell resistance mechanisms and they are often poorly tolerated. Utilising their proprietary technology, NuCana are developing new medicines, ProTides, designed to overcome key cancer resistance mechanisms and generate much higher concentrations of anti-cancer metabolites in cancer cells.