Oxford University researchers have collaborated with biopharmaceutical company NuCana to assess a novel chemotherapy drug derived from a fungus.
The results of a study published in Clinical Cancer Research has shown that the new drug NUC-7738, developed by NuCana, has 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 (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 bloodstream, so a minimal amount of cancer-destroying drugs 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 ProTide technology, 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.
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.
The results of the study 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 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 the drug are now being planned in partnership with NuCana.
