A new industry-academic partnership between the University of Oxford and biopharmaceutical company NuCana as found that chemotherapy drug NUC-7738, derived from a Himalayan fungus, has 40 times greater potency for killing cancer cells than its parent compound.
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 analog 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 tumor. 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 tumor. NuCana have utilized 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 analogs like Cordycepin, which are then later metabolized 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 tumors 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.
3′-deoxyadenosine (3′-dA; also known as cordycepin) is a nucleoside analog that has shown potent anti-cancer activity in non-clinical studies but has not been clinically developed because of its vulnerability to rapid degradation by the circulating enzyme adenosine deaminase (ADA) and its poor uptake into cancer cells.
The ProTide NUC-7738 is a pre-activated and protected nucleotide analog (3′-dA 5’monophosphate; 3′-dAMP) specifically designed to overcome the limitations of 3′-dA. NUC-7738’s phosphoramidate moiety renders it resistant to ADA degradation. Here we compared NUC-7738 to 3′-dA in several model systems prior to conducting a first-in-class dose-escalation/expansion study of NUC-7738 in patients with advanced cancers.
NUC-7738 demonstrated up to 185x greater anti-cancer potency than 3′-dA across a variety of cancer cells lines. Gene trap experiments showed that the intracellular activating enzyme adenosine kinase (ADK) and the hENT1 transporter were amongst the highest enriched genes for 3′-dA, whilst no enrichments for these genes were observed in NUC-7738 treated cells.
In support of this, in vitro inhibition assays showed that unlike 3′-dA, NUC-7738 is resistant to ADA breakdown, is not reliant on hENT1 transport for its cellular uptake, and is independent of ADK for its activity. As expected, RNA sequencing analysis demonstrated overlap between the MOA of NUC-7738 and 3′-dA; both cause cancer cell death via the intrinsic apoptosis pathway and suppression of pro-survival signaling. Further investigation of gene candidates was employed in ex-vivo cancer kidney cancer samples.
reference link: https://cancerres.aacrjournals.org/content/81/13_Supplement/931
More information: Hagen Schwenzer 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). DOI: 10.1158/1078-0432.CCR-21-1652