NUC-7738

This study demonstrates that combining long-read spatial transcriptomics with patient-derived organoid models provides a powerful and scalable approach for dissecting gene and isoform-level heterogeneity in ccRCC and for elucidating spatially resolved transcriptional responses to novel therapeutics.

P1/2, N=135, Recruiting, NuCana plc | N=94 --> 135 | Trial completion date: Jun 2024 --> Aug 2026 | Trial primary completion date: Jun 2024 --> Aug 2026

P1/2, N=94, Recruiting, NuCana plc | Trial completion date: Jan 2024 --> Jun 2024 | Trial primary completion date: Jan 2024 --> Jun 2024

NUC-7738 reduces secreted forms of PD-L1 whilst having no effect on cell surface protein levels. These in vitro results (melanoma cell line) were validated in the clinical setting, whereby ExoPD-L1 was reduced in plasma samples from patients treated with NUC-7738. These findings indicate that, by reducing sPD-L1 levels, NUC-7738 may have the potential to act as an immune sensitizer.

NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells.

Through the ability to reduce PI3K-p110, phosphorylated AktSer 473 , and phosphorylated GSK3β Ser9 and suppress β-catenin signalling, NUC-7738 exploits a key developmental process of AML, supressing the expansion and survival of LSCs. These results indicate that targeting LSCs with NUC-7738 may offer a successful therapeutic strategy for treating patients with leukemia.