Acelarin (fosgemcitabine palabenamide)

The damage associated with NUC-1031 may be potentiated by a second mechanism, via binding the RRM1 subunit of ribonucleotide reductase and perturbing the nucleotide pools; however, this may be mitigated by increased RRM1 expression. The implication of this was investigated in case studies from a Phase I clinical trial to observe whether baseline RRM1 expression in tumour tissue at time of diagnosis correlates with patient survival.

At the dose and schedule utilised for NUC-1031 in this study, the primary endpoint was not met with a longer OS with GemCis, despite a higher ORR with NUC-1031+cis. NUC-1031+cis was associated with more liver-related TEAEs, leading to early discontinuation. While these early liver events were more frequent in NUC-1031+cis, they were observed in both arms and are likely a combination of drug-induced liver toxicity, disease progression, and underlying liver dysfunction in this patient population.

Here, we report on CD44-targeting GEM nanotherapeutics obtained by encapsulating hydrophobic phosphorylated GEM prodrug (HPG), a single isomer of NUC-1031, into A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG demonstrates stability against degradation, enhanced internalization and inhibition toward CD44 cells, and increased accumulation in A549 lung tumor xenografts, leading to potent repression of orthotopic tumor growth, depleted toxicity and marked survival benefits. The targeted delivery of GEM prodrug using A6-mHPG is a highly appealing strategy to GEM cancer therapy.

Background: The nucleoside analog gemcitabine is used for the treatment of patients with lung cancer. NUC-1031 is a potent cytotoxic agent that directly causes DNA damage through generation of dFdCTP. In addition, these data demonstrate the NUC-1031 promotes adaptive changes that alter the recognition of cancer cells by the immune system. The release of DAMPs by NUC-1031 and increase in PD-L1 is predicted to engender an immune response, which might be further potentiated by immune checkpoint inhibition.