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Published on: October 13, 2023
rNAPc2 inhibits colorectal cancer in mice through tissue factor
Jingsong Zhao1, Gerard Aguilar, Servando Palencia
1Department of Research, Nuvelo, Inc., San Carlos, California 94070, USA. jzhao@nuvelo.com
Purpose:
Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel antithrombotic activity. TF is highly expressed in human colorectal tumors, and levels are positively correlated with disease progression.
Experimental Design:
To explore the therapeutic potential and mechanism of action of rNAPc2 during tumor growth and metastasis, we tested rNAPc2 in several experimental colorectal cancer models in mice.
Results:
Administration of rNAPc2 inhibited pulmonary metastasis in mice systemically disseminated with CT26 murine colon carcinoma cells in a dose-dependent fashion. Combining rNAPc2 with the cytotoxic agent 5-fluorouracil or bevacizumab (humanized anti-vascular endothelial growth factor monoclonal antibody) resulted in additive growth inhibition and simultaneous reduction of microvessel density in HCT116 human colorectal tumor xenografts in nude mice. Furthermore, rNAPc2 potentiated CPT-11 in inhibiting hepatic metastasis in nude mice with portal vein injection of HCT116 tumor cells. Long-term administration of rNAPc2 significantly suppressed spontaneous formation of intestinal tumors in Apc(Min/+) mice. Using a RNA interference approach, we showed that TF expression is necessary for rNAPc2-mediated inhibition of HCT116 human colorectal tumor xenograft growth in nude mice, indicating that the antitumor effect of rNAPc2 may be transduced through TF that is expressed on tumor cells.
Conclusions:
rNAPc2 is a potent anticancer agent when used in combination with chemotherapy or antiangiogenic therapy in mouse models of colorectal cancer, and TF positivity appears to be required for its activity.
Insights
Recombinant nematode anticoagulant protein c2 (rNAPc2) shows potent anticancer effects in colorectal cancer models. Its efficacy is enhanced when combined with chemotherapy or antiangiogenic therapy, requiring tissue factor (TF) for activity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Colorectal cancer (CRC) is a significant global health concern.
- Tissue Factor (TF) is highly expressed in CRC, correlating with disease progression.
- Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of the TF/Factor VIIa complex with antithrombotic properties.
Purpose of the Study:
- To investigate the therapeutic potential of rNAPc2 in colorectal cancer.
- To elucidate the mechanism of action of rNAPc2 in tumor growth and metastasis.
- To evaluate rNAPc2 in combination with standard therapies.
Main Methods:
- rNAPc2 was tested in experimental mouse models of colorectal cancer, including CT26 and HCT116 cell lines.
- Combination therapies included 5-fluorouracil, bevacizumab, and CPT-11.
- RNA interference was used to assess the role of TF in rNAPc2's antitumor effects.
Main Results:
- rNAPc2 demonstrated dose-dependent inhibition of pulmonary metastasis in mice.
- Combination therapy with rNAPc2 and chemotherapy/antiangiogenic agents resulted in additive tumor growth inhibition and reduced microvessel density.
- rNAPc2 potentiated chemotherapy in inhibiting hepatic metastasis.
- Long-term rNAPc2 administration suppressed spontaneous intestinal tumor formation.
- TF expression was necessary for rNAPc2-mediated tumor growth inhibition.
Conclusions:
- rNAPc2 exhibits potent anticancer activity in preclinical colorectal cancer models.
- Combination therapy with rNAPc2 enhances efficacy of chemotherapy and antiangiogenic agents.
- The antitumor effects of rNAPc2 are dependent on TF expression.
- rNAPc2 represents a promising therapeutic candidate for colorectal cancer treatment.
