185 Background: Fluoropyrimidines remain the cornerstone of systemic therapy for metastatic colorectal cancer (mCRC), but 5-fluorouracil (5-FU) efficacy is limited by acquired resistance and dose-limiting gastrointestinal toxicity. CF10 is a novel polymeric FdUMP engineered to directly deliver the active thymidylate synthase (TS) and topoisomerase-I (TOP1) inhibitor. Methods: CF10 was studied in clinically relevant preclinical models to determine its antitumor activity, to evaluate its tolerability and examine whether on-target pharmacodynamic (PD) readouts align with efficacy and tolerability signals. A comprehensive set of preclinical systems were used, including patient-derived CRC organoids, isogenic paired parental and 5-FU–resistant cell lines, mouse efficacy/tolerability models and a rat liver-metastasis model. Clinically translatable endpoints- tumor control and survival; body weight; and pharmacodynamic biomarkers of replication stress and DNA damage were measured. Results: In patient derived CRC organoids, CF10 demonstrated superior dose-responsive reductions in size and viability versus control and 5-FU. Consistent with its expected mechanism of action, CF10 activated replication-stress induced DNA damage response pathways, which may provide measurable PD markers for future studies. In three paired parental and 5-FU–resistant cell line models, CF10 effectively killed the 5-FU resistant cell lines, suggesting its potential to overcome drug resistance. In Vivo, CF10 significantly slowed tumor growth and extended survival in mouse models and primary patient derived cell line xenograft (CDX) models. Critically, body weight remained stable and serum chemistries did not worsen relative to 5-FU comparators, providing a strong tolerability signal. Additionally, in a rat liver-metastasis model, a dominant metastatic site, CF10 reduced hepatic tumor burden and improved survival versus control and 5-FU. Conclusions: Overall, CF10 shows preclinical antitumor activity in CRC, including in 5-FU–resistant models and a challenging liver-metastasis setting. These findings are complemented by encouraging tolerability and identification of measurable PD biomarkers. These findings provide promising critical preclinical data to support an early-phase I clinical evaluation of CF10. Median survival (days) in CRC CDX models (TXCC-201, TXCC-199). Median survival (days) CDX model Control 5FU CF10 Log-rank P(CF-10 vs 5-FU) n/arm TXCC201 18 29 43 0.00990 9 TXCC199 24 32 NR 0.0040 8 Medians from Kaplan–Meier; NR = not reached (no death of any mice); P from log-rank (CF-10 vs 5-FU); n/arm shown.
Sah et al. (Sat,) studied this question.