“These data are highly supportive of our strategy to develop NUC-3373 as a replacement for 5-FU, one of the most widely used medicines for the treatment of patients with cancer,” said Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer. “Based on the data from NuTide:302, we have initiated a randomized study in second-line CRC patients called NuTide:323 comparing NUFIRI plus bevacizumab to FOLFIRI plus bevacizumab, the global standard of care. Due to NUC-3373’s compelling biological rationale and strong clinical potential, we have also initiated the NuTide:303 study, investigating NUC-3373 in combination with either pembrolizumab in patients with various solid tumors or in combination with docetaxel in patients with non-small cell lung cancer.”
About NUC-3373
NUC-3373 is a phosphoramidate transformation of 5-fluorouracil, or 5-FU, which is designed to overcome the key limitations and pharmacologic challenges that hinder the clinical utility of 5-FU, with the aim of improving 5-FU’s efficacy, safety and administration challenges.
5-FU (and its other forms including capecitabine) is an inactive prodrug and its anti-cancer activity is dependent on its conversion to the active anti-cancer metabolite (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. TS is required to convert uridine (specifically dUMP) to thymidine (specifically dTMP), one of the four nucleotides that comprise DNA. The inhibition of TS results in an imbalance in the ratio of dUMP and dTMP, thereby disrupting DNA synthesis and repair, ultimately leading to cancer cell death. However, due to multiple limitations, 5-FU is not efficiently converted to FUDR-MP.
NUC-3373 generates much higher concentrations of FUDR-MP in patients’ cells. It also has a more convenient administration schedule and does not produce toxic levels of metabolites such as FBAL or FUTP (which are associated with hand-foot syndrome, neutropenia, mucositis and diarrhea) resulting in an improved safety profile.
In addition to preventing the synthesis of thymidine via TS inhibition, NUC-3373 treatment also results in the release of Damage Associate Molecular Patterns (DAMPs) and pro-inflammatory cytokines by cancer cells. These act as molecular signals to the immune system, encouraging them to kill cancer cells. Furthermore, NUC-3373 has been shown to induce the expression of PD-L1 on treated cells. In vitro experiments using NUC-3373 treated CRC cells co-cultured with immune cells have shown that NUC-3373 is able to potentiate the effects of PD-1 inhibitors, thus providing a strong scientific rationale for combining NUC-3373 and PD-1/PD-L1 inhibitors in patients.
About NuCana
NuCana is a clinical-stage biopharmaceutical company focused on significantly improving treatment outcomes for patients with cancer by applying our ProTide technology to transform some of the most widely prescribed chemotherapy agents, nucleoside analogs, into more effective and safer medicines. While these conventional agents remain part of the standard of care for the treatment of many solid and hematological tumors, they have significant shortcomings that limit their efficacy and they are often poorly tolerated. Utilizing our proprietary technology, we are developing new medicines, ProTides, designed
