CF10 Displayed Improved Activity Relative to 5-FU in a Mouse CRLM Model Under Conditions of Physiological Folate

Area of Science:

• Oncology
• Cancer Therapeutics
• Nanomedicine

Background:

• Colorectal cancer liver metastases (CRLM) affect at least 25% of patients.
• Fluoropyrimidine (FP) drugs like 5-fluorouracil (5-FU) offer survival benefits but limited long-term outcomes.
• Thymidylate synthase (TS) is the primary molecular target of FP drugs.

Purpose of the Study:

• To evaluate the potency of a nanoscale FP polymer, CF10, against colorectal cancer (CRC).
• To compare CF10's efficacy against 5-FU and trifluorothymidine (TFT).
• To investigate the dual-targeting mechanism of CF10/leucovorin (LV) and its potential for CRLM treatment.

Main Methods:

• TS/Top1 dual-targeting cytotoxic mechanism of CF10/LV confirmed via Western blot and immunofluorescence.
• Activation of the ATR/Chk1 pathway and induction of apoptosis by CF10/LV.
• In vivo studies in a CRLM model to assess eradication of liver metastases.

Main Results:

• CF10 demonstrated greater potency than expected, converting more directly to the TS-inhibitory metabolite FdUMP.
• CF10 showed a general potency advantage over 5-FU and TFT in CRC cell lines.
• CF10/LV co-treatment enhanced potency similarly to 5-FU/LV, with CF10/LV eradicating liver metastases without adverse effects.

Conclusions:

• Pre-clinical data indicate CF10 possesses a potency advantage over legacy FPs.
• CF10/LV exhibits a dual-targeting cytotoxic mechanism, activating DNA replication stress and inducing apoptosis.
• Early-phase clinical trials for CF10 in treating liver-metastatic CRC are warranted based on pre-clinical findings.